N3 alkylated benzimidazole derivatives as MEK inhibitors

ABSTRACT

Disclosed are compounds of the Formula I 
                         
and pharmaceutically acceptable salts and prodrugs thereof, wherein W, R 1 , R 2 , R 7 , R 8 , R 9  and R 10  are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed is a method of using such compounds in the treatment of hyperproliferative diseases in mammals, and pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. patent application Ser. No.10/387,879, filed Mar. 13, 2003, now abandoned which is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a series of alkylated(1H-Benzoimidazol-5-yl)-(4-substituted-phenyl)-amine derivatives thatare useful in the treatment of hyperproliferative diseases, such ascancer and inflammation, in mammals. This invention also relates to amethod of using such compounds in the treatment of hyperproliferativediseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

2. Summary of the Related Art

Cell signaling through growth factor receptors and protein kinases is animportant regulator of cell growth, proliferation and differentiation.In normal cell growth, growth factors, through receptor activation(i.e., PDGF or EGF and others), activate MAP kinase pathways. One of themost important and most well understood MAP kinase pathways involved innormal and uncontrolled cell growth is the Ras/ Raf kinase pathway.Active GTP-bound Ras results in the activation and indirectphosphorylation of Raf kinase. qRaf then phosphorylates MEK1 and 2 ontwo serine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2)(Ahn, et al., Methods in Enzymology 2001, 332, 417-431). Activated MEKthen phosphorylates its only known substrates, the MAP kinases, ERK1 and2. ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185and T183 for ERK2 (Ahn, et al., 2001, supra). Phosphorylated ERKdimerizes and then translocates to the nucleus where it accumulates(Khokhlatchev et al., Cell 1998, 93, 605-615). In the nucleus, ERK isinvolved in several important cellular functions, including but notlimited to nuclear transport, signal transduction, DNA repair,nucleosome assembly and translocation, and mRNA processing andtranslation (Ahn, et al., Molecular Cell 2000, 6, 1343-1354). Overall,treatment of cells with growth factors leads to the activation of ERK1and 2 which results in proliferation and, in some cases, differentiation(Lewis et al., Adv. Cancer Res. 1998, 74, 49-139).

In proliferative diseases, genetic mutations and/or overexpression ofthe growth factor receptors, downstream signaling proteins, or proteinkinases involved in the ERK kinase pathway lead to uncontrolled cellproliferation and, eventually, tumor formation. For example, somecancers contain mutations which result in the continuous activation ofthis pathway due to continuous production of growth factors. Othermutations can lead to defects in the deactivation of the activatedGTP-bound Ras complex, again resulting in activation of the MAP kinasepathway. Mutated, oncogenic forms of Ras are found in 50% of colonand >90% pancreatic cancers as well as many others types of cancers(Kohl, et al., Science 1993, 260, 1834-1837). Recently, bRaf mutationshave been identified in more than 60% of malignant melanoma (Davies, H.et al., Nature 2002, 417, 949-954). These mutations in bRaf result in aconstitutively active MAP kinase cascade. Studies of primary tumorsamples and cell lines have also shown constitutive or overactivation ofthe MAP kinase pathway in cancers of pancreas, colon, lung, ovary andkidney (Hoshino, R. et al., Oncogene 1999, 18, 813-822). Hence, there isa strong correlation between cancers and an overactive MAP kinasepathway resulting from genetic mutations.

As constitutive or overactivation of MAP kinase cascade plays a pivotalrole in cell proliferation and differentiation, inhibition of thispathway is believed to be beneficial in hyperproliferative diseases. MEKis a key player in this pathway as it is downstream of Ras and Raf.Additionally, it is an attractive therapeutic target because the onlyknown substrates for MEK phosphorylation are the MAP kinases, ERK1 and2. Inhibition of MEK has been shown to have potential therapeuticbenefit in several studies. For example, small molecule MEK inhibitorshave been shown to inhibit human tumor growth in nude mouse xenografts,(Sebolt-Leopold, et al., Nature-Medicine 1999, 5 (7), 810-816; Trachet,et al., AACR Apr. 6-10, 2002, Poster #5426; Tecle, H. IBC 2^(nd)International Conference of Protein Kinases, Sep. 9-10, 2002), blockstatic allodynia in animals (WO 01/05390 published Jan. 25, 2001) andinhibit growth of acute myeloid leukemia cells (Milella, et al., J.Clin. Invest., 2001, 108 (6), 851-859).

Small molecule inhibitors of MEK have been disclosed. At least thirteenpatent applications have appeared in the last several years: U.S. Pat.No. 5,525,625 filed Jan. 24, 1995; WO 98/43960 published Oct. 8, 1998;WO 99/01421 published Jan. 14, 1999; WO 99/01426 published Jan. 14,1999; WO 00/41505 published Jul. 20, 2000; WO 00/42002 published Jul.20, 2000; WO 00/42003 published Jul. 20, 2000; WO 00/41994 publishedJul. 20, 2000; WO 00/42022 published Jul. 20, 2000; WO 00/42029published Jul. 20, 2000; WO 00/68201 published Nov. 16, 2000; WO01/68619 published Sep. 20, 2001; and WO 02/06213 published Jan. 24,2002.

SUMMARY OF THE INVENTION

This invention provides for alkylated(1H-benzoimidazol-5-yl)-(4-substituted phenyl)-amine compounds ofFormula I, and pharmaceutically acceptable salts and prodrugs thereofthat are useful in the treatment of hyperproliferative diseases.Specifically, the present invention relates to compounds of Formula Ithat act as MEK inhibitors. Also provided is a method for treatment ofcancer. Also provided are formulations containing compounds of Formula Iand methods of using the compounds to treat a patient in need thereof.In addition, there are described processes for preparing the inhibitorycompounds of Formula I.

Accordingly, the present invention provides compounds of the Formula I:

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein:

------ is an optional bond, provided that one and only one nitrogen ofthe ring is double-bonded;

R¹, R², R⁹ and R¹⁰ are independently selected from hydrogen, halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³—NR⁴SO₂R⁶, —SO₂NR³R⁴,—NR⁴C(O)R³, —C(O)NR³ ^(R) ⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl,aryl, arylalkyl, heteoraryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,—O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,—O(CR⁴R⁵)_(m)-heterocyclyl and —NR⁴(CR⁴R⁵)_(m)-heterocyclyl, where eachalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclylportion is optionally substituted with one to five groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R³ is selected from hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, (CH₂)_(n)C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionallysubstituted with one to five groups independently selected from oxo,halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SR, —S(O)R″″, —SO₂R″″,—NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R′, R″ and R′″ independently are selected from hydrogen, lower alkyl,lower alkenyl, aryl and arylalkyl;

R″″ is selected from lower alkyl, lower alkenyl, aryl and arylalkyl; or

any two or R′, R″, R′″ or R″″ can be taken together with the atom towhich they are attached to form a 4 to 10 membered carbocyclic,heteroaryl or heterocyclic ring, each of which is optionally substitutedwith one to three groups independently selected from halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroaryalkyl, heterocyclyl, andheterocyclyalkyl; or

R³ and R⁴ can be taken together with the atom to which they are attachedto form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring,each of which is optionally substituted with one to three groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″—C(O)R′,—C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″,—NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or

R⁴ and R⁵ independently represent hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, each of whichis optionally substituted with one to three groups independentlyselected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R′″, —SO₂NR′R″, —C(O)R″″, —C(O)OR′,—OC(O)R′, —NR C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″,—NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁶ is selected from trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl portion is optionally substituted with one to five groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″,—SO₂R″″, —NR′R′, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R⁷ is selected from hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, whereeach alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl portion is optionally substituted with one to five groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —SO₂R³, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

W is selected from heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl),—C(O)(aryl), —C(O)(heteroaryl) and —C(O)(heterocyclyl), each of which isoptionally substituted with 1-5 groups independently selected from—NR³R⁴, —OR³, —R², and C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl,each of which is optionally substituted with 1 or 2 groups independentlyselected from —NR³R⁴ and —OR³;

R⁸ is selected from hydrogen, —SCF₃, —Cl, —Br, —F, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR³,—C(O)R³, —C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl and—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, where each alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionallysubstituted with one to five groups independently selected from oxo,halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(CN)NR³R⁴, —OR³ aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl;

m is 0, 1, 2, 3, 4 or 5; and

j is 1 or 2.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention are thosedescribed by the general Formula I set forth above, and thepharmaceutically acceptable salts and prodrugs thereof.

The present invention also provides compounds of Formula I in which R⁷is C₁-C₁₀ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylalkyl, C₃-C₇heterocycloalkyl or C₃-C₇ heterocycloalkylalkyl each of which can beoptionally substituted with 1-3 groups independently selected from oxo,halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —SO₂R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

The present invention also provides compounds of Formula I wherein R⁸ is—OCF₃, —Br or —Cl, R² is hydrogen, and R¹ is lower alkyl or halogen.

The present invention also provides compounds of Formula I wherein R⁹ ishydrogen or halogen, and R¹⁰ is hydrogen.

The present invention also provides compounds of Formula I wherein W is—C(O)OR³ or —C(O)NR⁴OR³.

The present invention also provides compounds of Formula II:

wherein W, R¹, R⁷, R⁸, R⁹ and R¹⁰ are as defined above for Formula I.

The present invention also provides compounds of Formula II in which R⁷is C₁-C₁₀ alkyl, C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylalkyl, each ofwhich can be optionally substituted with 1-3 groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —SO₂R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

The present invention also provides compounds of Formula II wherein R⁸is —OCF₃, —Br or —Cl, and R¹ is lower alkyl or halogen.

The present invention also provides compounds of Formula II wherein R⁹is hydrogen or halogen, and R¹⁰ is hydrogen.

The present invention also provides compounds of Formula II wherein W is—C(O)OR³ or —C(O)NR⁴OR³.

The present invention also provides compounds of Formula III:

wherein R¹, R², R⁷, R⁸ and R⁹ are as defined above for Formula I, and Ais —OR³ or —NR⁴OR³, wherein R³ and R⁴ are as defined above for FormulaI.

The present invention also provides compounds of Formula III in which R⁷is C₁-C₁₀ alkyl, C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylalkyl, each ofwhich can be optionally substituted with 1-3 groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —SO₂R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴,—NR³R⁴—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

The present invention also provides compounds of Formula III wherein R⁸is —OCF₃, —Br or —Cl, R² is hydrogen, and R¹ is lower alkyl or halogen.

The present invention also provides compounds of Formula III wherein R⁹is hydrogen or halogen.

The present invention also provides compounds of Formula III wherein R³is hydrogen or lower alkyl when A is —OR³; and R⁴ is hydrogen when A is—NR⁴OR³.

The present invention also provides compounds of Formula IIa:

wherein R¹, R², R¹, R⁸ and R⁹ are as defined above for Formula I, and Ais —OR³ or —NR⁴OR³, wherein R³ and R⁴ are as defined above for FormulaI.

The present invention also provides compounds of Formula IIIa in whichR⁷ is C₁-C₁₀ alkyl, C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylalkyl, each ofwhich can be optionally substituted with 1-3 groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —SO₂R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR R,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

The present invention also provides compounds of Formula IIIa wherein R⁸is —OCF₃, —Br or —Cl, R² is hydrogen, and R¹ is lower alkyl or halogen.

The present invention also provides compounds of Formula IIIa wherein R⁹is hydrogen or halogen.

The present invention also provides compounds of Formula IIIa wherein R³is hydrogen or lower alkyl when A is —OR³; and R⁴ is hydrogen when A is—NR⁴OR³.

The present invention also provides compounds of Formula IIIb:

wherein R¹, R⁷, R⁸ and R⁹ are as defined above for Formula I, and A is—OR³ or —NR⁴OR³, wherein R³ and R⁴ are as defined above for Formula I.

The present invention also provides compounds of Formula IIIb in whichR⁷ is C₁-C₁₀ alkyl, C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylalkyl, each ofwhich can be optionally substituted with 1-3 groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —SO₂R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

The present invention also provides compounds of Formula IIIb wherein R⁸is —OCF₃, —Br or —Cl, and R¹ is lower alkyl or halogen.

The present invention also provides compounds of Formula IIIb wherein R⁹is fluoro or chloro.

The present invention also provides compounds of Formula IIIb wherein R³is hydrogen or lower alkyl when A is —OR³; and R⁴ is hydrogen when A is—NR⁴OR³.

Except as expressly defined otherwise, the following definition of termsis employed throughout this specification.

By “C₁-C₁₀ alkyl”, “alkyl” and “lower alkyl” in the present invention ismeant straight or branched chain alkyl groups having 1-10 carbon atoms,such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, heptyl, octyl, and the like. Preferred alkylradicals are C₁₋₆ alkyl. More preferred alkyl radicals are C₁₋₃ alkyl.

By “C₂-C₁₀ alkenyl”, “lower alkenyl” and “alkenyl” means straight andbranched hydrocarbon radicals having from 2 to 10 carbon atoms and atleast one double bond and includes ethenyl, propenyl, 1-but-3-enyl,1-pent-3-enyl, 1-hex-5-enyl and the like. More preferred are loweralkenyl having 3-5 carbon atoms.

By “C₂-C₁₀ alkynyl”, “lower alkynyl” and “alkynyl” means straight andbranched hydrocarbon radicals having from 2 to 10 carbon atoms and atleast one triple bond and includes ethynyl, propynyl, butynyl,pentyn-2-yl and the like. More preferred are alkynyl having 3-5 carbonatoms.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

By “aryl” is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy,trifluoromethyl, aryl, heteroaryl, and hydroxy.

By “heteroaryl” is meant one or more aromatic ring systems of 5-, 6-, or7-membered rings which includes fused ring systems (at least one ofwhich is aromatic) of 5-10 atoms containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, or sulfur. Examples ofheteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups are optionally mono-, di-, or trisubstituted with,e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl,and hydroxy.

As used herein, the term “carbocycle”, “carbocyclyl”, “cycloalkyl” or“C₃-C₁₀ cycloalkyl” refers to saturated carbocyclic radicals havingthree to ten carbon atoms. The cycloalkyl can be monocyclic, or apolycyclic fused system, and can be fused to an aromatic ring. Examplesof such radicals include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. The cycloalkyl groups herein are unsubstituted or, asspecified, substituted in one or more substitutable positions withvarious groups. For example, such cycloalkyl groups may be optionallysubstituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

By “heterocycle” or “heterocyclyl” is meant one or more carbocyclic ringsystems of 5-, 6-, or 7-membered rings which includes fused ring systemsof 4-10 atoms containing at least one and up to four heteroatomsselected from nitrogen, oxygen, or sulfur, and with the proviso that thering of the group does not contain two adjacent O or S atoms. A fusedsystem can be a heterocycle fused to an aromatic group. Preferredheterocycles include, but are not limited to, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro moietiesare also included within the scope of this definition. The foregoinggroups, as derived from the groups listed above, may be C-attached orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). An example of a heterocyclicgroup wherein 2 ring carbon atoms are substituted with oxo (═O) moietiesis 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. For example, such heterocycle groups maybe optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkylor di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “arylalkyl” means an alkyl moiety (as defined above)substituted with one or more aryl moiety (also as defined above). Morepreferred arylalkyl radicals are aryl-C₁₋₃-alkyls. Examples includebenzyl, phenylethyl, and the like.

The term “heteroarylalkyl” means an alkyl moiety (as defined above)substituted with a heteroaryl moiety (also as defined above). Morepreferred heteroarylalkyl radicals are 5- or 6-memberedheteroaryl-C₁₋₃-alkyls. Examples include, oxazolylmethyl, pyridylethyland the like.

The term “heterocyclylalkyl” means an alkyl moiety (as defined above)substituted with a heterocyclyl moiety (also defined above). Morepreferred heterocyclylalkyl radicals are 5- or 6-memberedheterocyclyl-C₁₋₃-alkyls. Examples include tetrahydropyranylmethyl.

The term “cycloalkylalkyl” means an alkyl moiety (as defined above)substituted with a cycloalkyl moiety (also defined above). Morepreferred heterocyclyl radicals are 5- or 6-memberedcycloalkyl-C₁₋₃-alkyls. Examples include cyclopropylmethyl.

The term “Me” means methyl, “Et” means ethyl, “Bu” means butyl and “Ac”means acetyl.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic and basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of the present invention arethose that form non-toxic acid addition salts, i.e., salts containingpharmaceutically acceptable anions, such as the acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edislyate, estolate, esylate, ethylsuccinate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate(embonate), palimitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, tannate,tartrate, teoclate, tosylate, triethiodode, and valerate salts. Since asingle compound of the present invention may include more than oneacidic or basic moieties, the compounds of the present invention mayinclude mono, di or tri-salts in a single compound.

In the case of an acidic moiety in a compound of the present invention,a salt may be formed by treatment of a compound of the present inventionwith a basic compound, particularly an inorganic base. Preferredinorganic salts are those formed with alkali and alkaline earth metalssuch as lithium, sodium, potassium, barium and calcium. Preferredorganic base salts include, for example, ammonium, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts.Other salts of acidic moieties may include, for example, those saltsformed with procaine, quinine and N-methylglusoamine, plus salts formedwith basic amino acids such as glycine, ornithine, histidine,phenylglycine, lysine and arginine. An especially preferred salt is asodium or potassium salt of a compound of the present invention.

With respect to basic moieties, a salt is formed by the treatment of acompound of the present invention with an acidic compound, particularlyan inorganic acid. Preferred inorganic salts of this type may include,for example, the hydrochloric, hydrobromic, hydroiodic, sulfuric,phosphoric or the like salts. Preferred organic salts of this type, mayinclude, for example, salts formed with formic, acetic, succinic,citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic,D-glutamic, D-camphoric, glutaric, glycolic, phthalic, tartaric, lauric,stearic, salicyclic, methanesulfonic, benzenesulfonic,paratoluenesulfonic, sorbic, puric, benzoic, cinnamic and the likeorganic acids. An especially preferred salt of this type is ahydrochloride or sulfate salt of a compound of the present invention.

In the compounds of the present invention, where terms such as(CR⁴R⁵)_(m) or (CR⁴R⁵)_(t) are used, R⁴ and R⁵ may vary with eachiteration of m or t above 1. For instance, where m or t is 2, the terms(CR⁴R⁵)_(m) or (CR⁴R⁵), may equal —CH₂CH₂— or—CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)— or any number of similar moieties fallingwithin the scope of the definitions of R⁴ and R⁵.

Certain compounds of the present invention may have asymmetric centersand therefore exist in different enantiomeric forms. All optical isomersand stereoisomers of the compounds of the present invention, andmixtures thereof, are considered to be within the scope of theinvention. With respect to the compounds of the present invention, theinvention includes the use of a racemate, one or more enantiomericforms, one or more diastereomeric forms, or mixtures thereof. Thecompounds of the present invention may also exist as tautomers. Thisinvention relates to the use of all such tautomers and mixtures thereof.

The subject invention also includes isotopically-labeled compounds,which are identical to those recited in the present invention, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as2H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Futher, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compound of the present invention and prodrugsthereof can generally be prepared by carrying out procedures disclosedin the Schemes and/or in the Examples and Preparations below, bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

This invention also encompasses pharmaceutical compositions containing acompound of Formulas I-IIIb and methods of treating proliferativedisorders, or abnormal cell growth, by administering prodrugs ofcompounds of the present invention. Compounds of the present inventionhaving free amino, amido, hydroxy or carboxylic groups can be convertedinto prodrugs. Prodrugs include compounds wherein an amino acid residue,or a polypeptide chain of two or more (e.g., two, three or four) aminoacid residues is covalently joined through an amide or ester bond to afree amino, hydroxy or carboxylic acid group of compounds of the presentinvention. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithineand methionine sulfone. Additional types of prodrugs are alsoencompassed. For instance, free carboxyl groups can be derivatized asamides or alkyl esters. Free hydroxy groups may be derivatized usinggroups including but not limited to hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs ofhydroxy and amino groups are also included, as are carbonate prodrugs,sulfonate esters and sulfate esters of hydroxy groups. Derivatization ofhydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein theacyl group may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in J. Med. Chem., 1996, 39, 10. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

The invention also relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier. In one embodiment, saidpharmaceutical composition is for the treatment of cancer such as brain,lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck,renal, kidney, ovarian, prostate, colorectal, esophageal, testicular,gynecological or thyroid cancer. In another embodiment, saidpharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention also relates to a pharmaceutical composition for thetreatment of pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or the treatmentof pain in a mammal which comprises a therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier.

The invention also relates to a pharmaceutical composition for theprevention of blastocyte implantation in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treatinga disease related to vasculogenesis or angiogenesis in a mammal whichcomprises a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, and a pharmaceutically acceptable carrier. In oneembodiment, said pharmaceutical composition is for treating a diseaseselected from the group consisting of tumor angiogenesis, chronicinflammatory disease such as rheumatoid arthritis, atherosclerosis,inflammatory bowel disease, skin diseases such as psoriasis, eczema, andscleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity,age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi'ssarcoma and ovarian, breast, lung, pancreatic, prostate, colon andepidermoid cancer.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof. Inone embodiment, said method relates to the treatment of cancer such asbrain, lung, squamous cell, bladder, gastric, pancreatic, breast, head,neck, renal, kidney, ovarian, prostate, colorectal, esophageal,testicular, gynecological or thyroid cancer. In another embodiment, saidmethod relates to the treatment of a non-cancerous hyperproliferativedisorder such as benign hyperplasia of the skin (e.g., psoriasis),restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, in combination with an anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors,biological response modifiers, anti-hormones, angiogenesis inhibitors,and anti-androgens.

The invention also relates to a method of treating pancreatitis orkidney disease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of preventing blastocyteimplantation in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof. In one embodiment, said method is for treating adisease selected from the group consisting of tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salts, prodrugs and hydrates of saidcompounds, according to the methods of this invention include, forexample, patients that have been diagnosed as having psoriasis,restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML,pancreatic cancer, skin cancer, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system (e.g., cancer of the thyroid, parathyroid or adrenalglands), sarcomas of soft tissues, cancer of the urethra, cancer of thepenis, prostate cancer, chronic or acute leukemia, solid tumors ofchildhood, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter (e.g., renal cell carcinoma, carcinoma of the renalpelvis), or neoplasms of the central nervous system (e.g., primary CNSlymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas).

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of the present invention, or a pharmaceutically acceptablesalt or solvate or prodrug thereof, in combination with an amount of achemotherapeutic, wherein the amounts of the compound, salt, solvate, orprodrug, and of the chemotherapeutic are together effective ininhibiting abnormal cell growth. Many chemotherapeutics are presentlyknown in the art. In one embodiment, the chemotherapeutic is selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors, andanti-androgens.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder whichmethod comprises administering to the mammal an amount of a compound ofthe present invention, or a pharmaceutically acceptable salt or solvateor prodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of the compound of the invention in this combinationtherapy can be determined as described herein.

It is believed that the compounds of the present invention can renderabnormal cells more sensitive to treatment with radiation for purposesof killing and/or inhibiting the growth of such cells. Accordingly, thisinvention further relates to a method for sensitizing abnormal cells ina mammal to treatment with radiation which comprises administering tothe mammal an amount of a compound of the present invention orpharmaceutically acceptable salt or solvate or prodrug thereof, whichamount is effective is sensitizing abnormal cells to treatment withradiation. The amount of the compound, salt, or solvate in this methodcan be determined according to the means for ascertaining effectiveamounts of such compounds described herein.

The invention also relates to a method of and to a pharmaceuticalcomposition of inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloprotienase inhibitors are described in WO 96/33172, WO 96/27583,European Patent Application No. 97304971.1, European Patent ApplicationNo. 99308617.2, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO98/33768, WO 98/30566, European Patent Publication 606,046, EuropeanPatent Publication 931,788, WO 90/05719, WO 99/52910), WO 99/52889, WO99/29667, PCT International Application No. PCT/IB98/01113, EuropeanPatent Application No. 99302232.1, Great Britain Patent Application No.9912961.1, U.S. Pat. No. 5,863,949, U.S. Pat. No. 5,861,510, andEuropean Patent Publication 780,386, all of which are incorporatedherein in their entireties by reference. Preferred MMP-2 and MMP-9inhibitors are those that have little or no activity inhibiting MMP-1.More preferred, are those that selectively inhibit MMP-2 and/or MMP-9relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, and RS 13-0830.

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes, forexample, the abnormal growth of: (1) tumor cells (tumors) thatproliferate by expressing a mutated tyrosine kinase or overexpression ofa receptor tyrosine kinase; (2) benign and malignant cells of otherproliferative diseases in which aberrant tyrosine kinase activationoccurs; (3) any tumors that proliferate by receptor tyrosine kinases;(4) any tumors that proliferate by aberrant serine/threonine kinaseactivation; and (5) benign and malignant cells of other proliferativediseases in which aberrant serine/theroine kinase activation occurs.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

Representative compounds of the present invention, which are encompassedby the present invention include, but are not limited to the compoundsof the examples and their pharmaceutically acceptable acid or baseaddition salts or prodrugs thereof.

The examples presented below are intended to illustrate particularembodiments of the invention, and are not intended to limit the scope ofthe specification or the claims in any way.

An illustration of the preparation of compounds of the present inventionis shown in Schemes 1-4.

General synthetic methods which may be referred to for preparing some ofthe compounds of the present invention are provided in WO 00/42022. Theforegoing patent application is incorporated herein by reference in itsentirety. An illustration of the preparation of compounds of the presentinvention is shown in Schemes 1-4.

Scheme 1 illustrates the synthesis of compounds of the presentinvention. In step 1, the acid is nitrated using standard conditionspreferable fuming nitric acid in H₂SO₄. In step 2, the aniline isprepared by fluoride displacement with NH₄OH at room temperature inwater followed by careful acidification with concentrated mineral acidto pH near 0. In step 3, the ester is prepared by standard methodsincluding by not limited to Fisher Esterification (MeOH, H₂SO₄), andreaction with TMSCHN₂ in suitable organic solvents like PhMe/MeOH orTHF/MeOH. In step 4, the dianilino derivative is prepared by heating (60to 200° C.) the ester with an excess of the appropriate aniline neat orin an organic solvent like xylenes. For example, when R¹=Me and R²=H thepreferred method is stirring the ester with 10 equivalents aniline inxylenes at reflux until complete reaction. In step 5, the nitro arene isreduced to produce the diamine by standard reduction conditions,including by not limited to H₂, and Pd/C or Pd(OH)₂/C or Raney Nickel inorganic solvent like EtOH or THF, Fe in AcOH, Zn in AcOH or Zn, NH₄Cl(aqueous) in MeOH. In step 6, the diamine is cyclization by heating withformic acid neat or formamidine acetate in an appropriate solvent likeEtOH. Alternatively, when R¹ or R² does not equal halo the nitro arenecan be converted directly to the benzimidazole in step 7 by heating informic acid with Pd(OH)₂/C or other palladium source like Pd/C. In step8, a halide can be incorporated by standard methods, including but notlimited to NBS or NCS and pTsOH in organic cosolvents like THF and MeOH.In step 9, the benzimidazole is alkylated to give a near equal mixtureof N1 and N3 products which are separable by standard techniques,including, for example, chromatography and trituration. The alkylationis accomplished by use of an alkylating agent like an alkyl halide andbase like NaH, or K₂CO₃ in suitable organic solvent like DMF or THF attemperatures ranging from 0 to 80° C. R⁷ can be further modified byvarious synthetic methods known in the art, as exemplified below. Instep 10, the ester is hydrolysized by standard saponification methods.The acid is then converted to the desired hydroxamate in step 11 bystandard coupling procedures including but not limited to EDCI, HOBt orPyBOP and the appropriate hydroxylamine in suitable organic solventslike DMF, THF or methylene chloride.

Scheme 2 illustrates an example in which the R⁸ substituent is on theaniline prior to the coupling procedure with the nitro ester. Thereaction description is exactly like that for Scheme 1 except that thereis no need to incorporated R⁸ as it is present in the aniline from thebeginning.

In Scheme 3, the preparation of N3 alkyl amino benzimidazole derivativesis illustrated. In step 1, the terminal alkene of the N3 alkylatedbenzimidazole hydroxamate is dihydroxylated using a suitable oxidantlike OSO₄ in suitable solvent or KMnO₄ or I₂, AgOAc, AcOH, water. Thediol is then further oxidized in step 2 by NaIO₄ or Pb(OAc)₄ in suitablebiphasic mixture to give the aldehyde. Alternatively (step 3), thealkene can be directly converted to the aldehyde by standard methodsincluding but not limited to ozone/Me₂S, NaIO₄/OsO₄ or KMnO₄. In step 4,the amine is prepared by reductive amination using standard methods suchas Na(CN)BH₃, Na(OAc)₃BH, NMe₄BH(OAc)₃ with or without AcOH in asuitable solvent such as methylene chloride, acetonitrile or THF. Thepreferable reduction amination is to treat the aldehyde with amine,Me₄NBH(OAc)₃ and acetic acid in MeCN at room temperature.

Scheme 4 illustrates the preparation of compounds of the presentinvention where W is heterocyclic. In step 1, the methyl ester isconverted to the hydrazide by stirring with hydrazine in a suitablesolvent like EtOH at temperatures from 50 to 100° C. The desiredheterocyclic derivative is then prepared by cyclization with theappropriate reagent. For oxadiazole 21 the hydrazide is treated with anorthoformate like triethyl orthoformate, and an acid catalyst like pTsOHin a suitable organic solvent like EtOH at elevated temperatures(50-100° C.). For hydroxy oxadiazole 22 the hydrazide can be cyclizedwith phosgene or a phosgene equivalent like triphosgene or carbonyldiimidazole in a suitable organic solvent like toluene at temperaturesranging from 50 to 120° C. The mercapto oxadizaole 23 can be prepared byreaction with carbon disulfide, and base like KOH in suitable organicsolvent like EtOH at elevated temperatures (50-100° C.). The aminooxadiazole 24 can be made by reaction with BrCN and base like NaHCO₃, ina suitable biphasic solvent system like dioxane and water at roomtemperature. Finally, the substituted amino oxadiazole 25 can beprepared by first reacting the hydrazide with an appropriateisothiocyanate in a suitable organic solvent like DMF or THF attemperatures ranging from 25 to 100° C. The intermediate can be isolatedor can be cyclized directly with the treatment of EDCI or othercarbodiimide in suitable organic solvent like THF or DMF at temperaturesranging from room temperature to 80° C.

In Scheme 5, the preparation of keto benzimidazole derivatives isillustrated. In step 1, the methyl ester is converted to the benzylalcohol by standard reductive methods, preferably LAH in THF at 0° C. orNaBH₄ in EtOH:THF at room temperature. Oxidation to the aldehyde can beaccomplished in step 2 using MnO₂ in acetone:THF at 50° C. In step 3,organometallic reagents, such as organolithium reagents and Grignardreagents, can be added to the aldehyde in THF at low temperature (e.g.,−78° C.) to give the substituted benzyl alcohol. The keto derivativescan be prepared in step 4 by oxidation of the benyzl alcohol understandard conditions such as Swern or Dess-Martin oxidation.

The compounds of the present invention may have asymmetric carbon atoms.Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomer mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomeric mixtures andpure enantiomers are considered as part of the invention.

The activity of the compounds of the present invention may be determinedby the following procedure. N-terminal 6 His-tagged, constitutivelyactive MEK1 (2-393) is expressed in E. coli and protein is purified byconventional methods (Ahn et al., Science 1994, 265, 966-970). Theactivity of MEK1 is assessed by measuring the incorporation ofγ-³³P-phosphate from γ-³³P-ATP onto N-terminal His tagged ERK2, which isexpressed in E. coli and is purified by conventional methods, in thepresence of MEK1. The assay is carried out in 96-well polypropyleneplate. The incubation mixture (100 μL) comprises of 25 mM Hepes, pH 7.4,10 mM MgCl₂, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mMDTT, 5 nM MEK1, and 1 μM ERK2. Inhibitors are suspended in DMSO, and allreactions, including controls, are performed at a final concentration of1% DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5μCi γ-³³P-ATP/well) and incubated at ambient temperature for 45 minutes.An equal volume of 25% TCA is added to stop the reaction and precipitatethe proteins. Precipitated proteins are trapped onto glass fiber Bfilterplates, and excess labeled ATP is washed off using a Tomtec MACHIII harvestor. Plates are allowed to air-dry prior to adding 30 μL/wellof Packard Microscint 20, and plates are counted using a PackardTopCount. In this assay, compounds of the invention exhibited an IC₅₀ ofless than 50 micromolar.

The following compounds were evaluated in the above assay and found tobe active.

Compound #  8n 11b 11c 11p 18i 29c 29i 29s 29t 29bb 29lll 29mmm

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to 7 g/day,preferably about 0.05 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumor substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for example,interferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of treatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, or suspension, for parenteral injectionas a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Ester, Pa., 15^(th) Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

Representative examples of methods for preparing intermediates of theinvention are set forth below.

EXAMPLES Example 1

7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylicAcid cyclopropylmethoxy-amide (11a)

Step A: 2,3,4-Trifluoro-5-nitro-benzoic acid 2: A 3 liter three neckround bottom flask is charged with 125 mL H₂SO₄. Fuming nitric acid isadded (8.4 mL, 199 mmol) and the mixture gently stirred.2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portionsover 90 minutes. The dark brownish yellow solution is stirred for 60minutes at which time the reaction is complete. The reaction mixture ispoured into 1 liter of an ice water mixture and extracted with diethylether (3×600 mL). The combined organic extracts are dried (MgSO₄) andconcentrated under reduced pressure to give a yellow solid. The solid issuspended in hexanes and stirred for 30 minutes after which time it isfiltered to give 29 g (92%) of clean desired product as an off-yellowsolid: MS APCI (−) m/z 220 (M−1) detected.

Step B: 4-Amino-2,3-difluoro-5-nitro-benzoic acid 3: Ammonium hydroxidesolution (˜30% in water) (35 mL, 271 mmol) is added to a solution of2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 mL waterat 0° C. with stirring. Upon completion of ammonium hydroxide additionthe reaction mixture is warmed to room temperature with stirring. After2.5 hours, the reaction mixture is cooled to 0° C. and concentrated HClis carefully added until pH of reaction mixture is near 0. The reactionmixture is diluted with water (30 mL) and extracted with diethyl ether(3×50 mL). The combined organic extracts are dried (MgSO₄) andconcentrated under reduced pressure to give 14 g (95%) of pure desiredproduct: MS APCI (−) m/z 217 (M−1) detected.

Step C: 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4: A 2 Msolution of TMS diazomethane in hexanes (6.88 mL, 13.75 mmol) is addedto a suspension of 4-amino-2,3-difluoro-5-nitro-benzoic acid 3 (2.00 g,9.17 mmol) in 25 mL of 4:1 THF:MeOH at 0° C. under nitrogen atmosphere.Upon completion of addition, reaction mixture is warmed to roomtemperature. After 0.5 hours, excess TMS diazomethane is destroyed bythe careful addition of acetic acid. The reaction is then concentratedunder reduced pressure and dried in vacuo to give 1.95 g (92%) of puredesired product: MS APCI (−) m/z 231 (M−1) detected.

Step D: 4-Amino-3-fluoro-5-nitro-2-o-tolylamino-benzoic acid methylester 5a: 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (12.0g, 51.7 mmol) is suspended in xylenes (60 mL) and ortho-toluidine isadded (55.2 mL, 517 mmol). The reaction mixture is heated to reflux withstirring under a nitrogen atmosphere. After 36 hours, the reactionmixture is cooled to room temperature, diluted with diethyl ether andwashed with 10% aqueous HCl solution. The aqueous washings are extractedwith diethyl ether. The combined organic extracts are concentrated underreduced pressure. The residue is dissolved in methylene chloride andfiltered through silica gel in a fritted funnel, rinsing with methylenechloride. Three fractions are recovered. The first (2 liter) is nearlyclean by HPLC. The second (1 liter) and third (1 liter) fractions areonly partially pure. The first fraction is concentrated under reducedpressure and triturated with diethyl ether to give 11.2 g (68%) of cleandesired product as a bright yellow solid: MS APCI (−) m/z 318 (M−1)detected.

Step E: 7-Fluoro-6-o-tolylamino-1H-benzoimidazole-5-carboxylic acidmethyl ester 7a: 4-Amino-3-fluoro-5-nitro-2-o-tolylamino-benzoic acidmethyl ester 5a (1.57 g, 4.92 mmol), formic acid (25 mL, 26.5 mmol) and20% Pd(OH)₂/C (1.57 g, 2.95 mmol) in 25 mL EtOH are heating withstirring to 95° C. After 16 hours, the reaction mixture is cooled toroom temperature and 0.5 g 20% Pd(OH)₂/C and 10 mL formic acid added.The reaction mixture is heated to 95° C. with stirring. After 16 hours,the reaction mixture is cooled to room temperature and filtered throughCelite rinsing with EtOH. The filtrate is concentrated under reducedpressure until the desired product precipitates. The desired product iscollected by filtration. The filtrate is concentrated again until moredesired product precipitates. The product is collected by filtration.Repeated EtOH concentration, product filtration several times. Recovered1.09 g (74%) pure desired product: MS APCI (+) m/z 300 (M+1) detected;MS APCI (−) m/z 298 (M−1) detected.

Step F:7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester 8a:7-Fluoro-6-o-tolylamino-1H-benzoimidazole-5-carboxylic acid methyl ester7a (2.00 g, 6.68 mmol) is suspended in 1:1 THF/MeOH (60 mL) and cooledto −78° C. under a nitrogen atmosphere. A solution of NBS (1.20 g, 6.75mmol) in 1:1 THF/MeOH (5 mL) is added followed by a MeOH (5 mL) solutionof TsOH.H₂O (1.9 g, 10.0 mmol). After 30 minutes, the reaction mixtureis warmed to 0° C. and then after 1 hour warmed to room temperature.After 16 hours, more NBS (0.12 g, 0.67 mmol) is added and the reactionmixture is allowed to stir for 3 hours. The reaction mixture is quenchedby the addition of 10% Na₂S₂O₄ solution. After 30 minutes, the reactionmixture is diluted with water and ethyl acetate and the layersseparated. The aqueous layer is extracted with ethyl acetate. Thecombined organic extracts are dried (Na₂SO₄) and concentrated underreduced pressure. The recovered solid is triturated with methylenechloride to give 2.00 g (79%) pure desired product: MS APCI (+) m/z 380,378 (M+1 Br pattern) detected.

Step G:7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid 10a:7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester 8a (63 mg, 0.167 mmol) is suspended in MeOH (1.5 mL)and 20% NaOH (400 μl) is added. After 16 hours, the reaction mixture iscooled to 0° C. and 1 N HCl solution is added dropwise until pH is 2 to3. The reaction mixture is diluted with ethyl acetate and water and thelayers separated. The organic layer is washed with brine, dried (Na₂SO₄)and concentrated under reduced pressure to give 58 mg (95%) of desiredproduct: MS APCI (+) m/z 366, 364 (M+1 Br pattern) detected; MS APCI (−)m/z 364, 362 (M−1 Br pattern) detected.

Step H:7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11a:7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid 10a (48 mg, 0.132 mmol) is dissolved in 1:1 THF: methylene chloride(1 mL) and Hunig's base (0.23 μL, 1.32 mmol) is added followed by PyBOP(82 mg, 0.158 mmol). After a few minutes, cyclopropyl methylhydroxylamine hydrochloride (20 mg, 0.158 mmol) (WO 00/42022) is added.After the reaction is complete, the mixture is partitioned betweenmethylene chloride and saturated NaHCO₃ solution. The layers areseparated and the organic layer is washed with saturated NaHCO₃ andbrine. The organic layer is dried (Na₂SO₄) and concentrated underreduced pressure. After purification by FCC (elute with 20:1 methlenechloride/MeOH), 25 mg (45%) of pure desired product is isolated: MS ESI(+) m/z 435, 433 (M+1 Br pattern) detected; MS ESI (−) m/z 433, 431 (M−1Br pattern) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 8.02 (s,1H), 7.28 (s, 1H), 7.43 (d, 1H), 7.07 (dd, 1H), 6.36 (m, 1H), 3.70 (d,2H), 2.38 (s, 3H), 0.86 (m, 1H), 0.41 (m, 2H), 0.13 (m, 2H); ¹⁹F NMR(376 MHz, CDCl₃)-134.05 (s).

Example 2

7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester(27a)

Step A: 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic Acid Methyl Ester26a

4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (23.48 g, 101.1mmol), the product of Example 1, Step C, is suspended in xylenes (125mL) and aniline (92 mL, 1011 mmol) is added. The reaction mixture isstirred at 125° C. for 16 hours under N₂. The reaction mixture is cooledto room temperature and solids precipitate out of solution. The solidsare collected by filtration and are washed with xylenes and then diethylether. Recovered 22.22 g (72.78 mmol) of yellow solid which is puredesired product. The filtrate is concentrated under reduced pressure,redissolved in methylene chloride and flushed through a plug of silicagel eluting with methylene chloride. The desired fractions areconcentrated under reduced pressure to give a brown solid which istriturated with diethyl ether to give 5.47 g (17.91 mmol) of yellowsolid which is pure desired product. Combined product yield is 27.69 g(90%). MS APCI (−) m/z 304 (M−1) detected.

Step B: 7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acidmethyl ester 27a: 4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acidmethyl ester 26a (16.70 g, 54.71 mmol), formic acid (250 mL, 6.63 mol)and 20% Pd(OH)₂/C (9.00 g, 16.91 mmol) in ethanol (250 mL) are stirredat 40° C. for two hours under N₂ and then at 95° C. for 16 hours. Thereaction mixture is cooled to room temperature and filtered throughCelite rinsing with ethyl acetate. The filtrate is concentrated underreduced pressure to give a yellow solid. The solid is triturated withdiethyl ether to give 13.47 g (86%) of the desired product as a tansolid. MS APCI (+) m/z 286 (M+1) detected; MS APCI (−) m/z 284 (M−1)detected.

Example 3

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester (8b)

Step A: 6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 28a:7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester27a (4.99 g, 17.51 mmol) is dissolved in N,N-dimethylformamide (275 mL).N-bromosuccinimide (3.15 g, 17.70 mmol) is added as a solid and thereaction mixture is stirred at room temperature under N₂. After 30minutes, the reaction mixture is quenched by the addition of aqueoussaturated sodium bisulfite solution. The reaction mixture is then pouredinto a separatory funnel, diluted with water and ethyl acetate and thelayers separated. The aqueous layer is extracted with ethyl acetate. Thecombined organic extracts are washed three times with water, once withbrine and then are dried (Na₂SO₄) and concentrated under reducedpressure to yield 6.38 g (100%) of the pure desired product as a tansolid. MS ESI (+) m/z 364, 366 (M+Br pattern) detected.

Step B:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b:6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acidmethyl ester 28a (6.38 g, 17.51 mmol) is dissolved inN,N-dimethylformamide (275 mL). N-chlorosuccinimide (2.36 g, 17.70 mmol)is added as a solid and the reaction mixture is stirred at roomtemperature under N₂ until the reaction is complete (5-6 days). Thereaction mixture is quenched by the addition of aqueous saturated sodiumbisulfite solution to give a suspension. The resulting solids arecollected by filtration, washed with water and diethyl ether and driedunder reduced pressure to yield 6.07 g (87%) of the pure desired productas a beige solid. MS ESI (+) m/z 398, 400 (M+Br pattern) detected.

Example 4

6-(2,4-Dichloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester (8c)

7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester27a (1.00 g, 3.51 mmol) is suspended in 1:1 tetrahydrofuran/methanol (20mL) and cooled to −78° C. under N₂. TsOH.H₂O (3.00 g, 10.50 mmol) isadded followed by N-chlorosuccinimide (0.95 g, 7.08 mmol). After 10minutes, the reaction mixture is warmed to 0° C. to give a solution andthen 30 minutes later warmed to room temperature. After stirring for 16hours, the reaction is complete. The reaction mixture is quenched by theaddition of aqueous saturated sodium bisulfite solution and diluted withethyl acetate and water and the layers separated. The aqueous layer isextracted with ethyl acetate. The combined organic extracts are washedwith brine, dried (Na₂SO₄) and concentrated under reduced pressure. Theresulting solid residue is triturated with methylene chloride to yield awhite solid which is collected by filtration to yield 1.05 g (85%) ofthe pure desired product. MS ESI (+) m/z 355, 357 (M+Cl pattern)detected.

Example 5

6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester (8d)

Step A: 4-Amino-3-fluoro-2-(2-fluoro-phenylamino)-5-nitro-benzoic acidmethyl ester 5b: 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester4 (1.50 g, 6.46 mmol) is suspended in xylenes (7.5 mL) and2-fluoro-phenylamine (6.24 mL, 64.6 mmol) is added. The reaction mixtureis stirred at 140° C. under N₂. After stirring for 6 days, the reactionis complete. The reaction mixture is cooled to room temperature anddiluted with methylene chloride and filtered through a silica gel plugeluting with methylene chloride (1L) to give an orange filtrate. Thefiltrate is concentrated to dryness and then triturated with diethylether to yield a bright yellow solid. The trituration is repeated. Theyellow solid is collected to yield 1.08 g (52%) of the pure desiredproduct. MS APCI (−) m/z 322 (M−1) detected.

Step B:6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8d:4-Amino-3-fluoro-2-(2-fluoro-phenylamino)-5-nitro-benzoic acid methylester 5b is converted by the reduction/cyclization and brominationprocedures already described to yield the desired product. MS ESI (+)m/z 382, 384 (M+, Br pattern) detected.

Example 6

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester (8e)

7-Fluoro-6-o-tolylamino-3H-benzoimidazole-5-carboxylic acid methyl ester7a is converted by the procedure already described for bromination,except N-chlorosuccinimide is used instead of N-bromosuccinimide, toyield the desired product. MS ESI (+) m/z 334, 336 (M+, Cl pattern)detected.

Example 7

7-Fluoro-6-(2-methyl-4-trifluoromethoxy-phenylamino)-3H-benzoimidazole-5-carboxylicacid methyl ester (8f)

Step A.4-Amino-3-fluoro-2-(2-methyl-4-trifluoromethoxy-phenylamino)-5-nitro-benzoicacid methyl ester 12a: 4-Amino-2,3-difluoro-5-nitro-benzoic acid methylester 4 (0.50 g, 2.15 mmol) is suspended in xylenes (3 mL) and2-methyl-4-trifluoromethoxy-phenylamine (1.00 g, 5.23 mmol) is added.The reaction mixture is stirred at 140° C. under N₂. After stirring for7 days, the reaction is a mixture of starting material and product. Thereaction mixture is cooled to room temperature. The reaction mixture ispoured into a separatory funnel and diethyl ether and 10% aqueous HClare added and the layers separated. The aqueous phase is extracted withthree portions of diethyl ether. The combined diethyl ether layers aredried (MgSO₄) and concentrated under reduced pressure. The residue isredissolved in methylene chloride and flushed through a plug of silicagel eluting with methylene chloride. The filtrate is concentrated underreduced pressure to give a bright yellow solid. The solid is washed withdiethyl ether and the filtrate is concentrated under reduced pressureand the residue is further purified by FCC (eluting with 100% methylenechloride) to yield 0.39 g (45%) of the desired pure product as a yellowsolid. MS APCI (−) m/z 402 (M−1) detected.

Step B.7-Fluoro-6-(2-methyl-4-trifluoromethoxy-phenylamino)-3H-benzoimidazole-5-carboxylicacid methyl ester 8f:4-Amino-3-fluoro-2-(2-methyl-4-trifluoromethoxy-phenylamino)-5-nitro-benzoicacid methyl ester 12a is converted by the reduction/cyclizationprocedure already described to yield the desired product. MS APCI (+)m/z 384 (M+1) detected; MS APCI (−) m/z 382 (M−1) detected.

Example 8 Preparation of Hydroxylamines

Hydroxylamines useful for synthesizing compounds of the presentinvention may be prepared as follows

(i) O-(2-Methoxy-ethyl)-hydroxylamine

Step A: 2-(2-Methoxy-ethoxy)-isoindole-1,3-dione: DEAD (10 mL, 63 mmol)is added to a mixture of 2-methoxyethanol (5.0 mL, 63 mmol), PPh₃ (17 g,63 mmol), and N-hydroxyphthalimide (10 g, 62 mmol) in THF (170 mL). Theresulting orange solution is stirred 16 hours at room temperature. Thereaction mixture is concentrated in vacuo, and the solids are filteredwashing with CHCl₃. The filtrate is concentrated again, and the solidsare filtered washing with CHCl₃. This process is repeated until noprecipitate forms. The final yellowish solids are recrystallized fromEtOH to give the desired product (7.7 g, 55%).

Step B: O-(2-Methoxy-ethyl)-hydroxylamine: To a solution of2-(2-methoxy-ethoxy)-isoindole-1,3-dione (7.7 g, 35 mmol) in CH₂Cl₂ (30mL) at room temperature is added methylhydrazine (2.0 mL, 36 mmol). Theresulting solution is stirred for 16 hours at room temperature. Thewhite solids are filtered off. The solvent is carefully distilled offunder reduced pressure, and the concentrate is distilled under vacuum(20 torr, 57-58° C.) to afford the desired product (2.2 g, 68%).

(ii) The following hydroxylamines are prepared as described above usingthe appropriate alcohols. The isoindole-1,3-dione intermediates arepurified by flash chromatography:

O-(2-Isobutoxy-ethyl)-hydroxylamine is used directly withoutpurification.

O-(2-Pyrrolidin-1-yl-ethyl)-hydroxylamine is used directly withoutpurification.

O-(2-Piperidin-1-yl-ethyl)-hydroxylamine is purified by Kugelrohrdistillation (chamber temperature 140° C., 1 torr).

O-(2-Methylsulfanyl-ethyl)-hydroxylamine is purified by vacuumdistillation (76-78° C., 20 torr).

O-(2-Phenylsulfanyl-ethyl)-hydroxylamine is used directly withoutpurification.

O-(3-Methylsulfanyl-propyl)-hydroxylamine is used directly withoutpurification.

(iii) The following hydroxylamines are prepared from the appropriateisoindole-1,3-dione by oxidation using oxone (Tetrahedron Lett., 1981,22, 1287), and then deprotection as described above:

O-(2-Methanesulfonyl-ethyl)-hydroxylamine is used directly withoutpurification.

O-(2-Benzenesulfonyl-ethyl)-hydroxylamine is purified by flashchromatography (1% MeOH in CH₂Cl₂).

O-(3-Methanesulfonyl-propyl)-hydroxylamine is used directly withoutpurification.

O-(3-Phenylsulfanyl-propyl)-hydroxylamine is prepared fromPhSCH₂CH₂CH₂Br and N-hydroxyphthalimide by the patent procedure WO0018790 and then is deprotected by the procedure described above andused directly without purification.

O-(3-Benzenesulfonyl-propyl)-hydroxylamine is prepared from the aboveisoindole-1,3-dione through its oxidation with oxone followed bydeprotection as described above and is purified by flash chromatography(100% CH₂Cl₂ to 2% MeOH in CH₂Cl₂).

(v) O-(2-Morpholin-4-yl-ethyl)-hydroxylamine Dihydrochloride

Step A: O-(2-Bromo-ethyl)-hydroxylamine hydrobromide:2-(2-Bromo-ethoxy)-isoindole-1,3-dione is prepared from1,2-dibromoethane and N-hydroxyphthalimide as described in WO 00/18790,and is then subjected to the procedure in J. Org. Chem., 1963, 28, 1604to yield the desired product.

Step B: (2-Bromo-ethoxy)-carbamic acid tert-butyl ester: To a solutionof O-(2-bromo-ethyl)-hydroxylamine hydrobromide (100 mg, 0.45 mmol) anddi-t-butyl dicarbonate (110 mg, 0.49 mmol) in CH₂Cl₂ (1 mL) at roomtemperature is added Et₃N (0.08 mL, 0.56 mmol). The resulting suspensionis stirred for 16 hours room temperature. The reaction mixture isdiluted with EtOAc, washed with 1 N aqueous HCl and brine, dried overMgSO₄, filtered, concentrated, and purified by flash chromatography(100% CH₂Cl₂) to give the desired product (81 mg, 75%).

Step C: (2-Morpholin-4-yl-ethoxy)-carbamic acid tert-butyl ester: To asolution of (2-bromo-ethoxy)-carbamic acid tert-butyl ester (252 mg,1.05 mmol) in DMF (2 mL) at room temperature is added morpholine (0.14mL, 1.6 mmol). The reaction mixture is stirred for 7 hours at 50° C. Thereaction mixture is diluted with EtOAc, and washed with water. Theorganic layer is dried over MgSO₄, filtered, concentrated, and purifiedby flash chromatography (2% MeOH in CH₂Cl₂) to give the desired product(118 mg, 46%): MS APCI (+) m/z 247 detected.

Step D: 0-(2-Morpholin-4-yl-ethyl)-hydroxylamine dihydrochloride: To asolution of (2-morpholin-4-yl-ethoxy)-carbamic acid tert-butyl ester(118 mg, 0.48 mmol) in MeOH (1 mL) is added 4 M dioxane solution of HCl(2.4 mL, 9.60 mmol) at room temperature. The resulting solution isstirred for 16 hours at room temperature. After addition of additionalHCl (2.4 mL) followed by stirring for 4 hours, the reaction mixture isconcentrated in vacuo to give yellow solids (82 mg, 78%).

(vi) The isoindole-1,3-dione intermediates of the followinghydroxylamines are prepared from the appropriate alkyl halide andN-hydroxyphthalimide by the procedure described within J. HeterocyclicChem., 2000, 37, 827-830. The isoindole-1,3-diones are deprotected bythe procedure described above: O-but-3-enyl-hydroxylamine;O-(tetrahydro-furan-2-ylmethyl)-hydroxylamine;O-(3-methoxy-propyl)-hydroxylamine; andO-(3-benzyloxy-propyl)-hydroxylamine.

(vii) The following hydroxylamines are prepared as described in WO02/06213: O-(2-vinyloxy-ethyl)-hydroxylamine;2-aminooxy-2-methyl-propan-1-ol; 1-aminooxy-2-methyl-propan-2-ol;3-aminooxy-propan-1-ol; and (2-aminooxy-ethyl)-methyl-carbamic acidtert-butyl ester.

Example 9

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicAcid cyclopropylmethoxy-amide (11b)

Step A: 4-Amino-2-(2-chloro-phenylamino)-3-fluoro-5-nitro-benzoic acidmethyl ester 5b: 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester4 (2.00 g, 8.62 mmol) is suspended in xylenes (15 mL) and 2-chloroaniline (9.06 mL, 86.15 mmol) is added. The reaction mixture is heatedto 140° C. under a nitrogen atmosphere. After 6 days, the reactionmixture is cooled to room temperature, and diluted with ethyl acetate.The reaction mixture is washed with water, 10% HCl solution and brine.The organic layer is dried (MgSO₄) and concentrated under reducedpressure. The crude product is triturated with diethyl ether, twice, togive 0.35 g (12%) pure desired product as a brownish solid.

Step B: 4,5-Diamino-2-(2-chloro-phenylamino)-3-fluoro-benzoic acidmethyl ester 6a:4-Amino-2-(2-chloro-phenylamino)-3-fluoro-5-nitro-benzoic acid methylester 5b (0.30 g, 0.88 mmol) is suspended in AcOH (5 mL) and zinc dust(0.29 g, 4.42 mmol) is added. After 15 minutes, the reaction iscomplete. The reaction mixture is diluted with ethyl acetate andfiltered through Celite. The filtrate is washed with water, saturatedNaHCO₃, 10% K₂CO₃ and brine. The organic layer is dried (MgSO₄) andconcentrated under reduced pressure to give 0.13 g (48%) pure desiredproduct as a whitish brown foam.

Step C: 6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 7b:4,5-Diamino-2-(2-chloro-phenylamino)-3-fluoro-benzoic acid methyl ester6a (0.125 g, 0.404 mmol) is suspended in EtOH (2 mL) and formamidineacetate (63 mg, 0.605 mmol) is added. The reaction mixture is heated toreflux. After 16 hours, the reaction mixture is cooled to roomtemperature and diluted with ethyl acetate. The organic layer is washedwith water, saturated NaHCO₃, 10% K₂CO₃ and brine. The organic layer isdried (MgSO₄) and concentrated under reduced pressure to give 0.109 g(85%) pure desired product.

Step D:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b:6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5carboxylic acidmethyl ester 7b (55 mg, 0.172 mmol) is dissolved in 1:1 THF/MeOH (2 mL)and cooled to −780C under an atmosphere of nitrogen. TsOH.H₂O (49 mg,0.258 mmol) is added followed by NBS (31 mg, 0.174 mmol). After 10minutes, the reaction mixture is warmed to 0° C. and then 2 hours laterwarmed to room temperature. After 16 hours, the reaction mixture isquenched by the addition of 10% Na₂S₂O₃ and diluted with ethyl acetateand water. The layers are separated and the aqueous layer is extractedwith ethyl acetate. The combined organic extracts are dried (MgSO₄) andconcentrated under reduced pressure. The crude product is trituratedwith methylene chloride to give 58 mg (85%) of pure desired product as atan solid.

Step E:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid 10b:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b (58 mg, 0.146 mmol) is suspended in EtOH (2 mL) and1 mL 2 N NaOH is added. After 16 hours, the reaction mixture is dilutedwith ethyl acetate, water, and 10% HCl solution. The layers areseparated and the organic layer is washed with brine. The organic layeris dried (MgSO₄) and concentrated under reduced pressure. Triturationwith MeOH provides 22 mg (39%) pure desired product.

Step F:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (11b):6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid 10b (22 mg, 0.057 mmol) is dissolved in DMF (1 mL) and HOBt (9 mg,0.062 mmol) followed by triethyl amine (18 μL, 0.132 mmol) is added.Cyclopropyl methyl hydroxylamine hydrochloride (8 mg, 0.062 mmol) isadded followed by EDCI (14 mg, 0.074 mmol). After 16 hours, the reactionmixture is diluted with ethyl acetate and water and the layersseparated. The organic layer is washed with saturated NH₄Cl, brine,saturated NaHCO₃, water and brine. The organic layer is dried (MgSO₄)and concentrated under reduced pressure to give 23 mg (89%) pure desiredproduct. MS APCI (+) m/z 455, 453 (M+Br pattern) detected; MS APCI (−)m/z 453, 451 (M−Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 11.69(broad s, 1H), 8.43 (s, 1H), 7.62 (d, 1H), 7.28 (dd, 1H), 6.42 (m, 1H),3.63 (d, 2H), 1.03 (m, 1H), 0.48 (m, 2H), 0.19 (m, 2H); ¹⁹F NMR (376MHz, DMSO-d₆) −132.95 (s).

The following compounds are prepared by methods similar to thosedescribed in Example 1 and in this Example 9 by using the appropriatecarboxylic acid and the appropriate hydroxylamine:

8g

8h

8i

8j

8k

8l

8m

8n

Example 10

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide (29c)

Step A:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid methyl ester 9a and6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester: A solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b (150 mg, 0.38 mmol), iodomethane (28 μL, 0.45 mmol)and potassium carbonate (78 mg, 0.56 mmol) in dimethylformamide (1.5 mL)is stirred at 75° C. for one hour. The reaction mixture is diluted withethyl acetate, washed with saturated aqueous potassium carbonate (2×),brine, and dried (Na₂SO₄). Flash column chromatography (20:1 methylenechloride/ethyl acetate) provides 56 mg (36%) of the more mobile6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid methyl ester 9a as a white solid. ¹⁹F NMR (376 MHz, CD₃OD) −133.5(s). MS APCI (+) m/z 412, 414 (M+, Br pattern) detected. Also isolatedis 54 mg (35%) of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester as a white solid. ¹⁹F NMR (376 MHz, CD₃OD) −139.9 (s).MS APCI (+) m/z 412, 414 (M+, Br pattern) detected.

Step B:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid 10c:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid methyl ester 9a (56 mg, 0.14 mmol) is dissolved into 2:1 THF/water(3 mL ) and NaOH (0.55 mL, 1.0 M aqueous solution, 0.55 mmol) is added.After stirring for two hours the reaction is reduced to one-quarterinitial volume via rotary evaporation and the remainder diluted to 50 mLwith water. The aqueous solution is acidified to pH 2 by the addition of1.0 M aqueous HCl and extracted with 1:1 tetrahydrofuran/ethyl acetate(3×), dried (Na₂SO₄) and concentrated under reduced pressure to provide43 mg (79%) pure carboxylic acid as an off white solid. MS ESI (+) m/z397, 398 (M+, Br pattern) detected.

Step C:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-vinyloxy-ethoxy)-amide 29a:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid 10c (2.00 g, 5.0 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.776g, 7.5 mmol), HOBt (0.88 g, 6.5 mmol), triethylamine (1.61 mL, 2.3 mmol)and EDCI (1.3 g, 6.5 mmol) are dissolved in dimethylformamide (52 mL)and stirred at room temperature for 48 hours. The reaction mixture isdiluted with ethyl acetate, washed with water (3×), saturated potassiumcarbonate (2×), saturated ammonium chloride (2×), brine, dried (Na₂SO₄)and concentrated under reduced pressure to an off-white solid.Trituration of the solid with diethyl ether provides 2.18 g (90%)desired product as an off-white solid. MS ESI (+) m/z 483, 485 (M+Brpattern) detected.

Step D:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide 29c: Hydrochloric acid (14 mL, 1.0 Maqueous solution, 14 mmol) is added to a suspension of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-vinyloxy-ethoxy)-amide 29a (2.18 g, 4.50 mmol) in ethanol (50mL) and the reaction mixture allowed to stir for 24 hours. The reactionmixture is concentrated to dryness by rotary evaporation and the solidspartitioned between 3:1 ethyl acetate/tetrahydrofuran and saturatedpotassium carbonate. The aqueous phase is extracted with 3:1 ethylacetate/tetrahydrofuran (3×), the combined organics dried (Na₂SO₄), andconcentrated to provide 2.11 g (100%)6-(4-bromo-2chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide as an off-white solid. MS ESI (+) m/z 457,459 (M+, Br pattern) detected. ¹H NMR (400 MHz, MeOH-d₄) δ 8.26 (s, 1H),7.78 (s, 1H), 7.57 (d, 1H), 7.24 (dd, 1H), 6.40 (dd, 1H), 3.86 (s, 3H),3.79 (m, 2H), 3.49 (m, 2H). ¹⁹F NMR (376 MHz, MeOH-d₄)-133.68 (s).

Example 11

The following compounds are prepared by methods similar to thosedescribed in Example 10 by using methyl ester 8b and the appropriatealkylating agent (Step A) and the appropriate hydroxylamine (Step C):

29d

29e

29f

29g

29h

29i

29j

29k

291

29m

29n

29o

29p

29q

29r

29s

29t

29u

29v

29w

29x

29y

29z

29aa

29bb

29cc

29dd

29ee

29ff

29gg

29hh

29ii

29jj

29kk

29ll

29mm

29nn

29oo

29pp

29qq

29rr

29ss

29tt

29uu

29vv

29ww

29xx

29yy

29zz

29aaa

29bbb

29ccc

29ddd

29eee

29fff

29ggg

Example 12

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2,3-dihydroxy-propoxy)-amide (29hhh)

To a solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid allyloxy-amide 29tt (20 mg, 0.04 mmol) in 0.50 mL 4:1tetrahydrofuran/water is added OSO₄ (41 μL, 0.054 M solution in t-BuOH,0.002 mmol) followed by NMO (7 mg, 0.06 mmol). The solution is stirredat room temperature for eight hours after which time HPLC analysisshowed complete conversion to product. The solution is then stirred withsaturated NaHSO₃ and diluted with ethyl acetate. The organic phase isdried (Na₂SO₄). Purification by FCC (DCM −>20:1 DCM/MeOH) provided 16 mgdesired product as an off-white solid. MS ESI (+) m/z 487, 489 (M+, Brpattern) detected.

Example 13

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (3,4-dihydroxy-butoxy)-amide (29iii)

6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid but-3-enyloxy-amide 29uu is subjected to the dihydroxylation methoddescribed in Example 12. MS APCI (+) m/z 501, 503 (M+Br pattern)detected.

Example 14

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-methylamino-ethoxy)-amide TFA salt (29jjj)

Prepared from(2-{[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbonyl]-aminooxy}-ethyl)-methyl-carbamicacid tert-butyl ester 29ww by trifluoroacetic acid deprotection inmethylene chloride. MS APCI (+) m/z 470, 472 (M+, Br pattern) detected;¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 7.74 (s, 1H), 7.51 (d, 1H), 7.19(dd, 1H), 6.39 (dd, 1H), 4.11 (m, 2H), 3.97 (s, 3H), 3.12 (m, 2H), 2.72(s, 3H); ¹⁹F NMR (376 MHz, CD₃OD) −77.41 (s, 3F), −134.79 (s, 1F).

Example 15

The following compounds are prepared by methods similar to thosedescribed in Example 10 by using methyl ester 8a and the appropriatealkylating agent (Step A) and the appropriate hydroxylamine (Step C):

11c

11d

11e

11f

Example 16

The following compounds are prepared by methods similar to thosedescribed in Example 10 by using methyl ester Se and the appropriatealkylating agent (Step A) and the appropriate hydroxylamine (Step C):

11g

11h

11i

11j

11k

11l

Example 17

The following compounds are prepared by methods similar to thosedescribed in Example 10 by using methyl ester 8c and the appropriatealkylating agent (Step A) and the appropriate hydroxylamine (Step C):

11m

29kkk

Example 18

The following compounds are prepared by methods similar to thosedescribed in Example 10 by using methyl ester 8d and the appropriatealkylating agent (Step A) and the appropriate hydroxylamine (Step C):

29lll

29mmm

Example 19

6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-[4-(4-methyl-piperazin-1-yl)-butyl]-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (11o)

Step A:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylicacid methyl ester 9b:7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester 8a (0.915 g, 2.419 mmol) is suspended in DMF (18 mL)under an atmosphere of nitrogen. Bromopentene (0.430 mL, 3.629 mmol) andK₂CO₃ (0.502 g, 3.629 mmol) are added and the reaction mixture waswarmed to 80° C. After 1 hour, the reaction mixture is cooled to roomtemperature and poured into 100 mL of 1:1 ethyl acetate/diethyl ether.The organic layer is washed with water and brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The N3 and N1 alkylated productsare separated by flash column chromatography, eluted with 20:1 methylenechloride/ethyl acetate. Complete separation of the isomers is obtainedby performing two chromatographic separations. The higher R_(f) productis the N3 product 9b, while the lower R_(f) product is the N1 product.The recovery of the N3 product 9b is 0.415 g (38%): LC/MS ESI (+) m/z448, 446 (M+1 Br pattern) detected. The recovery of the N1 product was0.486 g (45%): LC/MS ESI (+) m/z 448, 446 (M+1 Br pattern) detected.

Step B:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylicacid 10d:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylicacid methyl ester 9b is dissolved in 1:1 THF/MeOH (10 mL) and 1 N NaOHsolution (2.3 mL) is added. After 5 hours, the organic solvents areremoved under reduced pressure and the residue diluted with water and100 mL 1:1 THF:ethyl acetate. The layers are separated and the aqueouslayer extracted with ethyl acetate. The combined organic extracts aredried (Na₂SO₄) and concentrated under reduced pressure to afford 0.39 g(100%) clean desired product as a light yellow solid.

Step C:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11f:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylicacid 10d (0.390 g, 0.902 mmol) is dissolved in 1:1 THF/methylenechloride (6 mL) and Hunig's base (0.346 mL, 1.985 mmol) is addedfollowed by PyBOP (0.563 g, 1.083 mmol). After 10 minutes, cyclopropylmethyl hydroxylamine hydrochloride (0.134 g, 1.083 mmol) is added. After16 hours, the reaction mixture is diluted with ethyl acetate and washedwith 0.1 N HCl, saturated NaHCO₃, and brine. The organic layer is dried(Na₂SO₄) and concentrated under reduced pressure. The crude yellowresidue is purified by FCC eluted with ethyl acetate to give 0.315 g(70%) pure desired product as a yellow solid: MS APCI (+) m/z 503, 501(M+1 Br pattern) detected.

Step D:6-(4-Bromo-2-methyl-phenylamino)-3-(4,5-dihydroxy-pentyl)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11m:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11f (0.307 g, 0.612 mmol) is dissolved in4:1 THF/water (8 mL) and 1.134 mL (0.061 mmol) of an 0.054 M OsO₄solution in t-BuOH iias added followed by NMO (0.093 g, 0.796 mmol).After 5 hours, the reaction mixture is quenched by the addition of 10%NaHS₂O₃ solution. After 10 minutes, the reaction mixture is filteredthrough Celite rinsing with ethyl acetate and methylene chloride. Thefiltrate is diluted with ethyl acetate and washed with 0.01 N HCl, andbrine. The organic layer is dried (Na₂SO₄) and concentrated underreduced pressure. The crude product is purified by FCC eluted with 9:1ethyl acetate/MeOH to give 0.244 g (74%) pure desired product.

Step E: 6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-(4-oxo-butyl)-3Hbenzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11n: To amixture of6-(4-bromo-2-methyl-phenylamino)-3-(4,5-dihydroxy-pentyl)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11 m (0.244 g, 0.456 mmol), THF (5 mL) andpH 7 phosphate buffer (3 mL) is added sodium periodate (0.195 g, 0.911mmol). After 16 hours, the reaction mixture is diluted with ethylacetate and washed with NaHCO₃, and brine. The organic layer is dried(Na₂SO₄) and concentrated under reduced pressure to give an orangesolid. Purification by FCC eluted with 4:1 methylene chloride/MeOHyields 0.189 g (82%) pure desired product as a yellow solid: MS APCI (+)m/z 505, 503 (M+1 Br pattern) detected; MS APCI (−) m/z 503, 501 (M−1 Brpattern) detected.

Step F:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-[4-(4-methyl-piperazin-1-yl)-butyl]-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11o:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-(4-oxo-butyl)-3Hbenzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11n (15 mg,0.030 mmol) is dissolved in MeCN (500 μL) and methylpiperazine (10 μl,0.089 mmol) is added followed by AcOH (5 μL, 0.089 mmol). After 5minutes, tetramethylammonium triacetoxyborohydride (12 mg, 0.045 mmol)is added. After 5 minutes, the reaction mixture is diluted with ethylacetate and washed with NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated under reduced pressure to give 12 mg (69%) ofpure desired product as a white solid. MS APCI (−) m/z 587, 585 (M−1 Brpattern) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.98 (s, 1H),7.30 (d, 1H), 7.08 (dd, 1H), 6.30 (d, 1H), 6.1 (broad singlet, 1H), 4.26(t, 2H), 3.64 (d, 2H), 3.37 (s, 1H), 2.45 (broad, 8H), 2.41 (s, 3H),2.38 (t, 2H), 2.28 (s, 3H), 1.95 (quin, 2H), 1.55 (quin, 2H), 0.98 (m,1H), 0.50 (qt, 2H), 0.22 (qt, 2H).

Example 20

The following compounds are prepared by methods similar to thosedescribed in Example 19 by using the appropriate alkenyl substitutedbenzimidazole and the appropriate amine in the reductive amination (stepF):

18a

18b

18c

18d

18e

18f

18g

18h

18i

18j

18k

18l

18m

18n

18o

18p

18q

18r

18s

18t

18u

18v

18w

18x

18y

18z

18aa

18bb

Example 21

6-(4-Bromo-2-methyl-phenylamino)-3-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-butyl]-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (18 cc)

To a solution of6-(4-bromo-2-methyl-phenylamino)-7-fluoro-3-(4-thiomorpholin-4-yl-butyl)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 181 (8 mg, 0.014 mmol) in 1:1:1water/acetone/MeOH (1 mL) is added NMO (1.6 mg, 0.014 mmol) and osmiumtetroxide (250 μL, 0.054 M solution in t-BuOH, 0.014 mmol). Afterstirring for 24 hours, the solution is diluted with saturated sodiumthiosulfate, stirred for 10 minutes and diluted with ethyl acetate. Thesolution is washed with brine (2×), dried (Na₂SO₄) and concentratedunder reduced pressure to a grey solid. FCC (10:1dichloromethane/methanol) provides 6 mg (71%) desired product as anoff-white solid. MS ESI (+) m/z 622, 624 (M+, Br pattern) detected.

Example 22

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-[4-(4-methyl-piperazin-1-yl)-butyl]-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (18dd)

A solution of6-(4-bromo-2-chloro-phenylamino)-3-(4-chloro-butyl)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 18ee (10 mg, 0.018 mmol), sodium iodide(14 mg, 0.092 mmol), and 1-methyl-piperazine (10 μL, 0.092 mmol) arestirred at 85° C. for three hours. The reaction mixture is diluted withethyl acetate and washed three times with water, washed twice withsaturated aqueous potassium carbonate, dried (Na₂SO₄) and concentratedunder reduced pressure to a yellow oil. Flash column chromatography (1:1dichloromethane/methanol followed by methanol followed by 20:1methanol/triethylamine) yields clean product (8 mg, 72%) as an off-whitefoam. MS ESI (+) m/z 607, 609 (M+, Br pattern) detected. ¹H NMR (400MHz, DMSO-d₆) δ 8.37 (s, 1H), 7.71 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H),6.40 (dd, 1H), 4.38 (t, 2H), 3.62 (d, 2H), 2.45 (broad, 8H), 2.41 (t,2H), 2.28 (s, 3H), 1.96 (m, 2H), 1.54 (m, 2H), 1.07 (m, 1H), 0.50 (d,2H), 0.22 (d, 2H).

Example 23

The following compounds are prepared by methods similar to thosedescribed in Example 22, using an appropriate amine and primary alkylchloride.

18ff

18gg

18hh

18ii

18jj

18kk

18ll

18mm

l8nn

18oo

18pp

18qq

18rr

18ss

18tt

18uu

18vv

18ww

18xx

18yy

18zz

18aaa

18bbb

18ccc

18ddd

18eee

18fff

Example 24

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3-oxazol-5-ylmethyl-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (18ggg)

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3-(2-oxo-ethyl)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (0.020 g, 0.046 mmol) is dissolved inmethanol (2 mL). Potassium carbonate (0.013 g, 0.093 mmol) and1-isocyanomethanesulfonyl-4-methyl-benzene (0.010 g, 0.051 mmol) areadded. The reaction mixture is stirred at reflux for 16 hours under N₂,then concentrated under reduced pressure. The residue is dissolved inethyl acetate and poured into a separatory funnel and washed with waterand brine. The combined aqueous layers are reextracted with ethylacetate (2×). The combined ethyl acetate layers are dried (Na₂SO₄,) andconcentrated under reduced pressure. The resulting solid was purified byflash column chromatography (eluting with 15:1 methylenechloride:methanol) to yield 0.011 g (50%) of the desired product. MSAPCI (+) m/z 470, 472 (M+, Cl pattern) detected; ¹H NMR (400 MHz, CDCl₃)δ 10.51 (br s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.23 (s,1H), 7.15 (d, 1H), 6.92 (dd, 1H), 6.31 (d, 1H), 6.11 (br s, 1H), 5.45(s, 2H), 3.62 (d, 2H), 2.40 (s, 3H), 0.87 (m, 1H), 0.49 (m, 2H), 0.20(m, 2H). ¹⁹F NMR (376 MHz, CDCl₃) −134.54 (s).

Example 25

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (18hhh)

Step A:6-(4-Bromo-2-chloro-phenylamino)-3-(2-tert-butoxycarbonyl-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b (0.50 g, 1.25 mmol) is dissolved in DMF (8 mL)under N₂ and K₂CO₃ (0.26 g, 1.88 mmol) is added followed by t-butylacrylate (1.84 mL, 12.54 mmol). The reaction mixture is heated to 90° C.with stirring. After 4 hours, the reaction mixture is cooled to roomtemperature and diluted with ethyl acetate. The organic layer is washedwith water (3×) and brine, dried (MgSO₄) and concentrated under reducedpressure. Purification by flash column chromatography eluted with 19:1methylene chloride:ethyl acetate provides 0.41 g (62%) desired product.

Step B:6-(4-Bromo-2-chloro-phenylamino)-3-(2-carboxy-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester TFA salt:6-(4-Bromo-2-chloro-phenylamino)-3-(2-tert-butoxycarbonyl-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester (0.050 g, 0.095 mmol) is dissolved in methylenechloride (0.5 mL) and TFA (0.5 mL) is added. After 45 minutes, thereaction mixture is concentrated to dryness to give 0.49 g (88%)desiredproduct: LC/MS ESI (+) m/z 472, 470 (M+Br pattern) detected; ¹H NMR (400MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.64 (d, 1H),7.29 (dd, 1H), 6.45 (dd, 1H), 4.55 (t, 2H), 2.89 (t, 2H).

Step C:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylicacid methyl ester: To solution of6-(4-bromo-2-chloro-phenylamino)-3-(2-carboxy-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester (60 mg, 0.13 mmol) in DMF (1.8 mL) is added HOBt-H₂O(24 mg, 0.16 mmol), Et₃N (0.043 mL, 0.31 mmol), pyrrolidine (0.011 mL,0.13 mmol), and EDCI (34 mg, 0.18 mmol) at room temperature. Theresulting yellow solution is stirred 16 hours at room temperature. Thereaction mixture is diluted with EtOAc and water, washed with sat'daqueous NH₄Cl, brine, sat'd aqueous NaHCO₃, and brine. The organic layeris dried over MgSO₄, filtered, and concentrated in vacuo to give a crudematerial which is purified by flash chromatography (3% MeOH in CH₂Cl₂)to afford 45 mg (67%) of the desired product: MS APCI (+) m/z 523, 525(M+, Br pattern) detected.

Step D:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylicacid: To a solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylicacid methyl ester (41 mg, 0.079 mmol) in THF/H₂O (1.5 mL/0.75 mL) isadded 0.20 mL (0.20 mmol) of 1 N aqueous LiOH at room temperature. Theresulting solution is stirred 16 hours. The reaction mixture isacidified with 1 N aqueous HCl (pH ˜2 to 3) and diluted with EtOAc. Theorganic layer is dried over MgSO₄, filtered, and concentrated in vacuoto give a crude product (42 mg) which is directly used without furtherpurification.

Step E:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 18hhh: The title compound is prepared from6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylicacid and O-cyclopropylmethyl-hydroxylamine hydrochloride by the standardcoupling procedure described in Step A: MS APCI (+) m/z 578, 580 (M+, Brpattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.42 (s,1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.28 (d, 1H), 6.39 (m,1H), 4.52 (t, 2H), 3.66 (d, 2H), 3.33 (t, 2H), 3.28 (t, 2H), 2.89 (t,2H), 1.83 (m, 2H), 1.76 (m, 2H), 1.06 (m, 1H), 0.49 (m, 2H), 0.22 (m,2H); ¹⁹F NMR (376 MHz, DMSO-d₆) −132.94 (s, 1F).

Example 26

The following compounds are prepared by methods similar to thosedescribed in Example 25 using methyl ester 8b and the appropriateamines:

18iii

18jjj

18kkk

Example 27

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide (11p)

Step A:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid methyl ester 11q:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b (0.25 g, 0.63 mmol) is dissolved inN,N-dimethylformamide (5 mL). 2-Brothomethyl-tetrahydro-pyran (0.34 g,1.88 mmol) and potassium carbonate (0.26 g, 1.88 mmol) are added and thereaction mixture is stirred at 60° C. for 12 hours under N₂. Thereaction mixture is poured into a separatory funnel, diluted with ethylacetate and water and the layers separated. The ethyl acetate layer iswashed with water and brine, dried (Na₂SO₄) and concentrated underreduced pressure. The resulting solid residue is triturated with diethylether to yield a pale yellow solid (N3 regioisomer by NMR) and a yellowfiltrate (mixture of N1 and N3 regioisomers by NMR). The solids arecollected and washed with diethyl ether to yield 0.12 g (37%) of thepure desired N3 regioisomeric product as a pale yellow solid. MS ESI (+)m/z 496, 498 (M+, Br pattern) detected.

Step B:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid 11 r:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid methyl ester 11q is suspended in 4:1 tetrahydrofuran/water (2.5 mL)and aqueous 1 M LiOH is added (2.5 mL). After stirring at roomtemperature for 16 hours, the reaction mixture is homogeneous and thereaction is complete. The reaction mixture is cooled to 0° C., dilutedwith water and aqueous 2 M HCl is added dropwise until the pH of thesolution is 1-2, at which time it turns to a suspension. The reactionmixture is poured into a separatory funnel and diluted with ethylacetate/tetrahydrofuran and water and the layers separated. The aqueouslayer is extracted with ethyl acetate. The combined organic layers arewashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure to yield 0.11 g (100%) of the pure desired product as a whitesolid. MS ESI (+) m/z 482, 484 (M+, Br pattern) detected.

Step C:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid (2-vinyloxy-ethoxy)-amide 11s:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid 11r (0.11 g, 0.23 mmol) is dissolved in N,N-dimethylformamide (2mL). HOBT (0.037 g, 0.27 mmol) and triethylamine (0.094 mL, 0.68 mmol)are added. Then O-(2-vinyloxy-ethyl)-hydroxylamine (0.028 g, 0.27 mmol)and EDCI (0.056 g, 0.29 mmol) are added and the reaction mixture isstirred at room temperature under N₂ until HPLC shows the reaction iscomplete (2-3 days). The reaction mixture is poured into a separatoryfunnel, diluted with ethyl acetate and water and the layers separated.The ethyl acetate layer is washed successively with aqueous saturatedNH₄Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water(1×), and brine (1×), dried (Na₂SO₄) and concentrated under reducedpressure. The resulting solid is purified by FCC (eluting with 15:1methylene chloride:methanol) to yield 0.039 g (79%) of the pure desiredproduct as an off-white solid. MS ESI (+) m/z 567, 569 (M+, Br pattern)detected.

Step D:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide 11p:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylicacid (2-vinyloxy-ethoxy)-amide 11s (0.039 g, 0.068 mmol) is dissolved inethanol (2 mL) and aqueous 2 M HCl (200 uL) is added. The reactionmixture is stirred at room temperature for 30 minutes. The reactionmixture is diluted with water and then neutralized with aqueous 2 M NaOH(˜200 uL) until pH 7 and concentrated under reduced pressure. Theresidue is partitioned between ethyl acetate and brine in a separatoryfunnel and the layers separated. The ethyl acetate layer is dried(Na₂SO₄) and concentrated under reduced pressure to yield 0.034 g (91%)of the pure desired product as an off-white solid. MS ESI (+) m/z 541,543 (M+, Br pattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 8.29 (s, 1H),7.75 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.40 (dd, 1H), 4.40 (dd, A ofABX pattern, 1H), 4.28 (dd, B of ABX pattern, 1H), 3.92 (m, X of ABXpattern, 1H), 3.66 (t, 2H), 3.35 (m, 1H), 1.89 (m, 1H), 1.76 (m, 1H),2.28 (s, 3H), 1.54 (m, 3H), 1.30 (m, 1H). ¹⁹F NMR (376 MHz, CD₃OD)−134.87 (s).

Example 28

The following compounds are prepared by methods similar to thatdescribed in Example 27 by using the appropriate methyl ester andalkylating agent (Step A) and the appropriate hydroxylamine in (Step C).

11t

11u

11v

11w

11x

11y

11z

11aa

Example 29

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide (11bb)

Step A:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylicacid methyl ester 11cc:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b (1.55 g, 3.89 mmol) is dissolved in 15 mL DMF underN₂. K₂CO₃ (0.70 g, 5.06 mmol) is added followed by methyl vinyl sulfone(0.41 mL, 4.67 mmol). After stirring 16 hours at room temperature, thereaction mixture is diluted with ethyl acetate and water. The layers areseparated and the organic layer is washed with water (3×) and brine. Thecombined aqueous washes are extracted with ethyl acetate. The combinedorganic extracts are dried (MgSO₄) and concentrated under reduced.Purification by dissolving the residue in methylene chloride andprecipitating with diethyl ether, repeated several times, provides 1.16g (59%) pure desired product as a yellow solid: MS APCI (+) m/z 506, 504(M+Br pattern) and 400, 398 (M−methyl ethyl sulfone Br pattern).

Step B:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11bb:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylicacid methyl ester 11cc is subjected to methods previously described togive6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide: MS APCI (+) m/z 561, 559 (M+Br pattern)and MS APCI (−) m/z 559, 557 (M- Br pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 11.75 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.62(d, 1H), 7.28 (dd, 1H), 6.40 (dd, 1H), 4.78 (t, 2H), 3.82 (t, 2H), 3.62(d, 2H), 3.07 (s, 3H), 1.02 (m, 1H), 0.49 (m, 2H), 0.21 (m, 2H); ¹⁹F NMR(376 MHz, DMSO-d₆) −132.66 (s).

Example 30

The following compounds were prepared similarly using the appropriatemethyl ester and Michael acceptor and methods described previously.

11dd

11ee

11ff

11gg

11hh

11ii

11jj

11kk

11ll

11mm

11nn

Example 31

[6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-5-yl]-(4-bromo-2-methyl-phenyl)-amine(24a)

Step A:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid hydrazide 20a:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8a (0.051 g, 0.135 mmol) is suspended in EtOH (5 mL)and hydrazine hydrate (0.118 g, 2.023 mmol) is added. The reactionmixture is heated at reflux for 16 hours. The reaction mixture isconcentrated under reduced pressure and purified by FCC eluted with 97:3ethyl acetate:MeOH to give 0.041 g (81%) of clean desired product: LC/MSESI (+) m/z 378, 380 (M+Br pattern) detected.

Step B:[6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-5-yl]-(4-bromo-2-methyl-phenyl)-amine24a:6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid hydrazide 20a (0.041 g, 0.109 mmol) is suspended in 1,4-dioxane(1.5 mL) and 36 μL of a 3 M solution of cyanogen bromide in methylenechloride is added. NaHCO₃ (9 mg, 0.109 mmol) in water (1.5 mL) is thenadded. After 16 hours, the reaction mixture is diluted with water andbrine and extracted with THF. The combined organic extracts are dried(Na₂SO₄) and concentrated under reduced pressure. Purification by FCCeluted with 98:2 ethyl acetate:MeOH provides 24 mg (55%) of pure desiredproduct as a yellow solid: LC/MS ESI (+) m/z 403, 405 (M+Br pattern)detected; ¹H-NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 8.42 (s, 1H), 7.94(s, 1H), 7.74 (s, 1H), 7.36 (s, 2H), 7.33 (d, 1H), 7.15 (d, 1H), 6.40(bs, 1H), 2.34 (s, 3H).

Example 32

[6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-S-yl]-(4-chloro-2-methyl-phenyl)-amine(24b)

[6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-5-yl]-(4-chloro-2-methyl-phenyl)-amine24b is prepared as described in example 31 starting with6-(4-chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8e. LC/MS ESI (+) m/z 359, 361 (M+Cl pattern)detected; ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.00 (bs, 1H), 7.78(bs, 1H) 7.48 (s, 2H), 7.22 (s, 1H), 7.04 (d, 1H), 6.48 (bs, 1H), 2.37(s, 3H).

Example 33

[6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-S-yl]-(4-bromo-2-chloro-phenyl)-amine(24c)

[6-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1H-benzoimidazol-5-yl]-(4-bromo-2-chloro-phenyl)-amine24c is prepared as described in example 31 starting with6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b. MS APCI (+) m/z 425, 423 (M+Br pattern) and MSAPCI (−)m/z 423, 421 (M- Br pattern) detected.

Example 34

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid hydrazide (20b)

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid hydrazide 20b is prepared as described in example 31, step A from6-(4-chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8e. LC/MS ESI (+) m/z 334, 336 (M+Cl pattern)detected; ¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (bs, 1H), 9.98 (s, 1H), 8.40(s, 1H), 8.17 (bs, 1H), 7.64 (bs, 1H), 7.20 (s, 1H), 7.03 (d, 1H), 6.41(bs, 1H), 4.49 (s, 2H), 2.23 (s, 3H).

Example 35

5-[6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-[1,3,4]oxadiazol-2-ol(22a)

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid hydrazide 20b (0.050 g, 0.150 mmol) is suspended in PhMe (2 mL) anda 20% phosgene solution in PhMe (0.24 mL, 0.45 mmol) is added. Thereaction mixture is stirred at reflux under N₂ for 1 hour and thencooled to room temperature. The reaction mixture is quenched by theaddition of a 1:1 mixture of THF and 10% HCl (20 mL). The layers areseparated and the aqueous layer is extracted with THF (3×). The combinedorganic layer is washed with brine, dried (Na₂SO₄) and concentratedunder reduced pressure to give 54 mg (99%) of desired product as ayellow solid: LC/MS ESI (+) m/z 360, 362 (M+Cl pattern) detected; ¹H NMR(400 MHz, DMSO-d₆) δ 12.64 (s, 1H), 8.83 (s, 1H), 7.88 (s, 1H), 7.30 (s,1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.38 (dd, 1H), 2.30 (s, 3H).

Example 36

(4-Chloro-2-methyl-phenyl)-(4-fluoro-6-[1,3,4]oxadiazol-2-yl-1H-benzoimidazol-5-yl)-amine(21a)

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid hydrazide 20b (0.048 g, 0.144 mmol) is suspended in 3 mL absoluteEtOH and HC(OEt)₃ (0.60 mL, 3.54 mmol) is added followed by catalyticpTsOH.H₂O. The reaction mixture is heated to reflux under N₂. After 2hours, the reaction mixture is cooled to room temperature andconcentrated under reduced pressure. Purification by flash columnchromatography (97:3 ethyl acetate:MeOH) provides 36 mg (73%) desiredproduct as a light yellow solid. LC/MS ESI (+) m/z 344, 346 (M+Clpattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (bs, 1H), 9.39 (s,1H), 8.49 (s, 1H), 8.10 (bs, 1H), 7.78 (bs, 1H), 7.20 (d, 1H), 7.00 (dd,1H), 6.41 (bs, 1H), 2.18 (s, 3H).

Example 37

5-[6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-[1,3,4]oxadiazole-2-thiol(23a)

6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid hydrazide 20b (0.050 g, 0.150 mmol) is suspended in 3 mL absoluteEtOH and cooled to 0° C. under N₂. CS₂ is added (26 mg, 0.346 mmol)followed by powdered KOH (8 mg, 0.150 mmol). After stirring at 0° C. for30 minutes, the reaction mixture is heated to reflux. After 3.5 hours,the reaction mixture is quenched by the addition of water, followed bythe addition of ethyl acetate and 1N HCl. The layers are separated andthe aqueous layer is extracted with ethyl acetate. The combined organicextracts are dried (Na₂SO₄) and concentrated under reduced pressure togive the desired product as a yellow solid: LC/MS ESI (+) m/z 376, 378(M+Cl pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.92(s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 6.98 (d, 1H), 6.29 (d, 1H), 2.28(s, 3H).

Example 38

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methylamide (11oo)

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid 10c (0.029 g, 0.076 mmol) is dissolved in N,N-dimethylformamide(1.1 mL). HOBT (0.016 g, 0.10 mmol), triethylamine (0.028 mL, 0.20mmol), methylamine (0.059 mL, 0.12 mmol, 2 M solution intetrahydrofuran), and EDCI (0.019 g, 0.10 mmol) are added consecutivelyto the reaction mixture at room temperature. The solution is stirred atroom temperature for 16 hours under N₂. The reaction mixture is pouredinto a separatory funnel and diluted with ethyl acetate and water andthe layers separated. The ethyl acetate layer is washed successivelywith aqueous saturated NH₄Cl (2×), brine (1×), aqueous saturated sodiumbicarbonate (2×), water (1×), and brine (1×), dried (MgSO₄) andconcentrated under reduced pressure. The resulting solid is purified byFCC (eluting with 19:1 methylene chloride:methanol) to yield 0.013 g(42%) of the pure desired product. MS APCI (+) m/z 397, 399 (M+, Brpattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (broad s, 1H), 8.69(m, 1H), 8.41 (s, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.30 (dd, 1H), 6.50(dd, 1H), 2.76 and 2.75 (s and s, 3H total, amide rotamers). ¹⁹F NMR(376 MHz, DMSO-d₆) −132.69 (s).

Example 39

The following compounds are prepared using methods similar to thatdescribed above in Example 38 by using the appropriate carboxylic acidand amine. In those cases that contain two amine functionalities, theappropriate mono-Boc protected amine is used in the coupling reactionand the Boc group is later removed in a final step under standard TFAdeprotection conditions.

11pp

11qq

11rr

11ss

11tt

11uu

11vv

11ww

11xx

Example 40

[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-methanol(10e)

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid methyl ester 8b (1.06 g, 2.65 mmol) is suspended in tetrahydrofuran(25 mL) and cooled to −78° C. Lithium aluminum hydride (8.03 mL, 8.03mmol, 1M solution in tetrahydrofuran) is added dropwise to the reactionmixture. After stirring for 10 minutes at −78° C., the reaction mixtureis warmed to 0° C. and becomes a homogeneous solution. The reactionmixture is stirred for 5 minutes at 0° C. and then cooled again to −78°C. The reaction mixture is quenched with MeOH, diluted with Rochelle'ssalt, warmed to room temperature and stirred for 1 hour. The reactionmixture is then poured into a separatory funnel, diluted with ethylacetate, and the layers separated. The aqueous phase is extracted withethyl acetate. The combined ethyl acetate layers are dried (Na₂SO₄) andconcentrated under reduced pressure to yield 0.98 g (100%) of the puredesired product as a pale yellow solid. MS ESI (+) m/z 370, 372 (M+, Brpattern) detected.

Example 41

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde(10f)

[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-methanol10e (0.96 g, 2.58 mmol) is dissolved in tetrahydrofuran/acetone (1:1, 15mL), and MnO₂ (2.24 g, 25.8 mmol) is added. The reaction mixture isstirred at 50° C. for 10 hours under N₂. The reaction mixture isfiltered through silica gel and eluted with methylene chloride/methanol(10:1, 1 L). The filtrate is concentrated under reduced pressure to asmall volume and then filtered through an Acrodisc syringe filter toremove small amounts of MnO₂ that passed through the silica gel. Thefiltrate is concentrated under reduced pressure and the residue ispurified by flash column chromatography (eluting with 20:1 methylenechloride:methanol) to yield 0.81 g (85%) of the pure desired product asa bright yellow solid. MS ESI (+) m/z 368, 370 (M+, Br pattern)detected.

Example 42

1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-hydroxy-ethanone(10g)

Step A:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol10i: To a solution of tributyl-methoxymethoxymethyl-stannane (864 mg,2.37 mmol, prepared by the procedure reported in J. Org. Chem. 1988, 53,4131) in THF (8 mL) at −780C is added n-BuLi (0.94 mL, 2.35 mmol, 2.5 Msolution in hexane). After stirring for 3 minutes, a solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde10h (59 mg, 0.15 mmol) in THF (2 mL) is added at −78° C. After stirringfor 40 minutes at −78° C., the reaction is quenched with saturatedaqueous NH₄Cl at −78° C., warmed to room temperature, and diluted withEtOAc. The organic layer is washed with brine, dried over MgSO₄,filtered, concentrated, and purified by flash chromatography (1.5% MeOHin CH₂Cl₂) to give the desired product (45 mg, 64%): MS APCI (+) m/z458, 460 (M+, Br pattern) detected.

Step B:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone10j: A solution of1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol10i (44 mg, 0.096 mmol) and the Dess-Martin periodinane (49 mg, 0.12mmol) in CH₂Cl₂ (1.5 mL) is stirred for 1.5 hours at room temperature.The reaction mixture is diluted with ether (3 mL). Saturated aqueousNaHCO₃ (1 mL) containing sodium thiosulfate pentahydrate (74 mg) isadded. The resulting mixture is stirred for 10 minutes and diluted withEtOAc. The organic layer is washed with saturated aqueous NaHCO₃ andbrine, dried over MgSO₄, filtered, and concentrated in vacuo to give acrude material which is purified by flash chromatography (1.5% MeOH inCH₂Cl₂) to afford the desired product (31 mg, 71%): MS APCI (+) m/z 456,458 (M+, Br pattern) detected.

Step C:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-hydroxy-ethanone10g: A mixture of1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone10j (15 mg, 0.033 mmol), 10% aqueous HCl (0.3 mL), methanol (0.01 mL),and water (0.05 mL) is stirred for 3 days at room temperature. Thereaction mixture is neutralized with saturated aqueous NaHCO₃, anddiluted with EtOAc. The organic layer is washed with brine, dried overMgSO₄, filtered, concentrated in vacuo, and purified by flashchromatography (1.5% MeOH in CH₂Cl₂) to afford the desired prouduct (7.3mg, 54%): MS APCI (+) m/z 412, 414 (M+, Br pattern) detected; ¹H NMR(400 MHz, acetone-d₆) δ 8.64 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.58(d, 1H), 7.31 (dd, 1H), 6.59 (dd, 1H), 4.94 (s, 2H), 4.06 (s, 3H); ¹⁹FNMR (376 MHz, acetone-d₆) −132.45 (s, 1F).

Example 43

1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-hydroxy-ethanone(10k)

Step A:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol101:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde10f is treated with tributyl-methoxymethoxymethyl-stannane according tothe procedure described in Example 42, Step A to yield compound 101. MSAPCI (+) m/z 444, 446 (M+, Br pattern) detected.

Step B:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone10m: To a solution of oxalyl chloride (0.11 mL, 0.22 mmol) in CH₂Cl₂ (1mL) at −78° C. is added DMSO (0.016 mL, 0.22 mmol). After stirring for 3minutes, a solution of1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol10l (25 mg, 0.056 mmol) in methylene chloride (1 mL) is added. Theresulting solution is stirred for 30 minutes at −780C. TEA (0.1 mL, 0.71mmol) is added. The reaction mixture is slowly warmed to roomtemperature, stirred for 5 minutes at room temperature, and diluted withwater and CH₂Cl₂. The organic layer is separated, dried over MgSO₄,filtered, and concentrated to give the crude product which is directlyused without further purification.

Step C:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-hydroxy-ethanone10k:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone10m is deprotected according to the procedure described in Example 42,Step C to yield compound 10k. MS APCI (+) m/z 398, 400 (M+, Br pattern)detected; ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.52 (d,1H), 7.22 (dd, 1H), 6.53 (dd, 1H), 4.90 (m, 2H); ¹⁹F NMR (376 MHz,CD₃OD) −133.96 (s, 1F).

Example 44

1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanone(10n)

Step A:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanol10o: To a solution of lithiomethyl ethyl ether in THF (6 mL) (preparedfrom 4,4′-di-tert-butylbiphenyl (585 mg, 2.20 mmol), Li (18 mg, 2.59mmol), and EtOCH₂Cl (0.20 mL, 2.05 mmol) by the procedure reported inTetrahedron 1996, 52, 1643) is added a solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde10f (29 mg, 0.080 mmol) in THF (1 mL) at −78° C. The resulting solutionis stirred for 1 hour and then quenched with saturated aqueous NH₄Cl at−78° C., warmed to room temperature, and extracted with EtOAc. Theorganic layer is washed with brine, dried over MgSO₄, filtered,concentrated in vacuo, and purified by flash chromatography (100% CH₂Cl₂to 3% to 5% MeOH in CH₂Cl₂) to give the desired product (15 mg, 44%): MSAPCI (+) m/z 428, 430 (M+, Br pattern) detected.

Step B:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanone10n: The title compound is prepared from1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-ethoxy-ethanol10o according to the procedure described in Example 42, Step B exceptthat the reaction mixture is not treated with saturated aqueous NaHCO₃containing sodium thiosulfate pentahydrate. MS APCI (+) m/z 426, 428(M+, Br pattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.04(s, 1H), 7.51 (d, 1H), 7.21 (dd, 1H), 6.51 (dd, 1H), 4.76 (s, 2H), 3.57(q, 2H), 1.19 (t, 3H); ¹⁹F NMR (376 MHz, CD₃OD) −133.96 (s).

Example 45

1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxy-ethanone(10p)

1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxy-ethanone10p is prepared from6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde10f and lithiomethyl methyl ether by the procedures described in Example44. MS APCI (+) m/z 412, 414 (M+, Br pattern) detected.

Example 46

2-Benzyloxy-1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethanone(10q)

Step A:2-Benzyloxy-1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethanol10r: To a solution of benzyloxymethyllithium in THF (2 mL, prepared fromn-Bu₃SnCH₂OBn (505 mg, 1.23 mmol) and n-BuLi (0.49 mL, 1.22 mmol, 2.5 Msolution in hexane) by the procedure reported in J. Am. Chem. Soc. 1978,100, 1481) is added a solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde10f (51 mg, 0.14 mmol) in THF (3 mL) at −78° C. The resulting solutionis stirred for 1 hour at −78° C. The reaction is quenched with saturatedaqueous NH₄Cl, and extracted with EtOAc. The organic layer is dried overMgSO₄, filtered, concentrated in vacuo, and purified by flashchromatography (100% CH₂Cl₂ to 3% MeOH in CH₂Cl₂) to afford the desiredproduct (46 mg, 68%): MS APCI (+) m/z 490, 492 (M+, Br pattern)detected.

Step B:2-Benzyloxy-1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethanone10q: The title compound is prepared from2-benzyloxy-1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethanol10r by the procedure described in Example 42, Step B except that thereaction mixture is not treated with saturated aqueous NaHCO₃ containingsodium thiosulfate pentahydrate: MS APCI (+) m/z 488, 490 (M+, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.02 (s, 1H),7.51 (d, 1H), 7.26 (m, 5H), 7.19 (dd, 1H), 6.46 (dd, 1H), 4.77 (s, 2H),4.58 (s, 2H); ¹⁹F NMR (376 MHz, CD₃OD) −134.52 (s).

Example 47

1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methanesulfonyl-ethanone(10s)

Step A:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methanesulfonyl-ethanol10t: To a solution of methyl sulfone (65 mg, 0.68 mmol) in THF (1.5 mL)is added a solution of n-BuLi (0.27 mL, 0.68 mmol, 2.5 M solution inhexane) at −78° C. After stirring for 5 minutes, HMPA (0.1 mL) is added.After stirring for additional 10 minutes, a solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde10f (26 mg, 0.069 mmol) in THF (1 mL) is added. The resulting solutionis stirred for 1.5 hours at −78° C. The reaction is quenched withsaturated aqueous NH₄Cl, warmed to room temperature, and diluted withEtOAc. The organic layer is washed with water, dried over MgSO₄,filtered, concentrated in vacuo, and purified by flash chromatography(3% MeOH in CH₂Cl₂) to give the crude desired product (31 mg, 96%) whichis used directly without further purification: MS APCI (+) m/z 462, 464(M+, Br pattern) detected.

Step B:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methanesulfonyl-ethanone10s: The title compound is prepared from1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methanesulfonyl-ethanol10t by the procedure described in Example 42, Step B except that thereaction mixture is not treated with saturated aqueous NaHCO₃ containingsodium thiosulfate pentahydrate: MS APCI (+) m/z 460, 462 (M+, Brpattern) detected; ¹H NMR (400 MHz, acetone-d₆) δ 8.44 (s, 1H), 8.33 (s,1H), 7.59 (s, 1H), 7.32 (d, 1H), 6.68 (dd, 1H), 5.00 (s, 1H), 3.15 (s,3H); ¹⁹F NMR (376 MHz, acetone-d₆) −132.97 (s).

Example 48

1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethane-1,2-diol(10u)

Step A:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-(isopropoxy-dimethyl-silanyl)-ethanol10v: To a solution of the Grignard reagent prepared from Mg andchloromethyl dimethylisopropoxy silane (Org. Synth. 1992, 69, 96) [4.4mL, 3.26 mmol, 0.74 M solution (based on 90% purity)] in THF, is added asolution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde10f (200 mg, 0.54 mmol) in THF (1 mL) at −78° C. After stirring for 1hour at −78° C., the reaction is quenched with saturated aqueous NH₄Cl,and extracted with EtOAc. The organic layer is dried over MgSO₄,filtered, concentrated in vacuo to afford the crude desired productwhich is directly used without further purification.

Step B:1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-ethane-1,2-diol10u: To the crude1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-(isopropoxy-dimethyl-silanyl)-ethanol10v in MeOH-THF (5 mL-5 mL) is added KHCO₃ (54 mg, 0.54 mmol), and KF(74 mg, 1.27 mmol), and 30% aqueous H₂O₂ (0.20 mL) at room temperature.After stirring for 3.5 hours at room temperature, the reaction mixtureis diluted with water, and extracted with EtOAc. The organic layer isdried over MgSO₄, filtered, concentrated in vacuo, and purified by flashchromatography (8% to 10% MeOH in CH₂Cl₂) to give the desired product(74 mg, 34%): MS APCI (+) m/z 400, 402 (M+, Br pattern) detected; ¹H NMR(400 MHz, CD₃OD) δ 8.20 (s, 1H), 7.62 (broad s, 1H), 7.47 (d, 1H), 7.14(dd, 1H), 6.30 (d, 1H), 4.96 (t, 1H), 3.64 (m, 2H); ¹⁹F NMR (376 MHz,CD₃OD) −136.87 (s).

Example 49

[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-pyridin-2-yl-methanol(10w)

To a solution of 2-bromopyridine (0.10 mL, 1.04 mmol) in THF (3 mL) at−78° C. is added n-BuLi (0.39 mL, 0.98 mmol, 2.5 M solution in hexane).After stirring for 10 minutes at −78° C., a solution of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde10h (25 mg, 0.064 mmol) in THF (1 mL) is added. The resulting reactionmixture is stirred for 1.5 hours at −78° C., quenched with saturatedaqueous NH₄Cl, and extracted with EtOAc. The organic layer is dried overMgSO₄, filtered, concentrated in vacuo, and purified by flashchromatography (2.5% MeOH in CH₂Cl₂) to afford the desired product (18mg, 62%): MS APCI (+) m/z 461, 463 (M+, Br pattern) detected; ¹H NMR(400 MHz, CD₃OD) δ 8.31 (d, 1H), 8.16 (s, 1H), 7.65 (m, 3H), 7.38 (d,1H), 7.10 (m, 1H), 7.00 (dd, 1H), 6.11 (dd, 1H), 6.05 (s, 1H), 3.94 (s,3H); ¹⁹F NMR (376 MHz, CD₃OD) −135.79 (s).

Example 50

(4-Bromo-2-chloro-phenyl)-(4-fluoro-6-oxazol-5-yl-1H-benzoimidazol-5-yl)-amine(10x)

Step A:[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazol-5-yl]-methanol10y:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylicacid methyl ester 11 cc (0.300 g, 0.594 mmol) is suspended in a mixtureof EtOH (6 mL) and THF (4 mL) under N₂. NaBH₄ (0.112 g, 2.97 mmol) isadded. After approximately 4 days stirring, reaction mixture is quenchedby the addition of AcOH until the reaction mixture reaches pH 7. Thereaction mixture is concentrated to dryness under reduced pressure andthe residue partitioned between ethyl acetate and water. The layers areseparated and the organic layer is washed with water (3×), brine, anddried (Na₂SO₄). The organic layer is concentrated under reduced pressureuntil a white precipitate forms which is collected by filtration to give0.225 g (79%) clean desired product: LC/MS ESI (+) m/z 478, 476 (M+Brpattern) detected.

Step B:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde10z:[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazol-5-yl]-methanol10y (0.050, 0.105 mmol) is dissolved in 1:1 THF:acetone (2 mL) under N₂and MnO₂ (0.046 g, 0.524 mmol) is added. The reaction mixture is stirredat room temperature for 16 hours, and then at 55° C. for 5 hours.Additional MnO₂ (0.046 g, 0.524 mmol) is added and the reaction mixturestirred at 55° C. for 2 hours. The reaction mixture is concentrated todryness and the residue dissolved in 10:1 methylene chloride:MeOH. Thesolution is filtered through a silica gel plug eluted with 10:1methylene chloride:MeOH. The resulting filtrate is concentrated underreduced pressure to give 41 mg (82%) desired product as a bright yellowsolid.

Step C:(4-Bromo-2-chloro-phenyl)-(4-fluoro-6-oxazol-5-yl-1H-benzoimidazol-5-yl)-amine10×:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde10z (0.025 g, 0.053 mmol) is suspended in MeOH (2 mL) and K₂CO₃ (0.015g, 0.105 mmol) is added followed by tosylmethyl isocyanide (0.011 g,0.058 mmol). The reaction mixture is heated to reflux under N₂ for 16hours. After cooling, additional tosylmethyl isocyanide (0.011 g, 0.058mmol) is added and the reaction mixture heated to reflux under N₂ for 16hours. The reaction mixture is cooled to room temperature, concentratedunder reduced pressure and dissolved in ethyl acetate. The organicsolution is washed with water and brine. The combined aqueous washes areextracted with ethyl acetate. The combined organic extracts are dried(Na₂SO₄) and concentrated under reduced pressure. Purification by flashcolumn chromatography eluted with 20:1 methylene chloride:MeOH provides4 mg (18%) desired product 10× and 1 mg (4%)(4-bromo-2-chloro-phenyl)-[4-fluoro-1-(2-methanesulfonyl-ethyl)-6-oxazol-5-yl-1H-benzoimidazol-5-yl]-amine.

(4-Bromo-2-chloro-phenyl)-(4-fluoro-6-oxazol-5-yl-1H-benzoimidazol-5-yl)-amine 10x. LC/MS ESI (+) m/z 409, 407 (M+Br pattern)detected; ¹H NMR (400 MHz, MeOH-d₄)

8.33 (s, 1H), 8.24 (s, 1H), 7.94 (bs, 1H), 7.51 (d, 1H), 7.33 (s, 1H),7.07 (dd, 1H), 6.14 (dd, 1H).

(4-Bromo-2-chloro-phenyl)-[4-fluoro-1-(2-methanesulfonyl-ethyl)-6-oxazol-5-yl-1H-benzoimidazol-5-yl]-amine.LC/MS ESI (+) m/z 515, 513 (M+Br pattern) detected; ¹H NMR (400 MHz,MeOH-d₄)

8.39 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.52 (d, 1H), 7.37 (s, 1H),7.07 (m, 1H), 6.14 (dd, 1H), 3.83 (t, 2H), 2.99 (s, 3H), 1.18 (t, 2H).

Example 51

(4-Bromo-2-chloro-phenyl)-[4-fluoro-6-(3H-imidazol-4-yl)-1H-benzoimidazol-5-yl]-amine(10aa)

Step A:(4-Bromo-2-chloro-phenyl)-{4-fluoro-1-(2-methanesulfonyl-ethyl)-6-[4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-1H-benzoimidazol-5-yl}-amine10bb:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde10z (0.050 g, 0.107 mmol) is suspended in EtOH (0.5 mL) under N₂ andtosylmethyl isocyanide (0.020 g, 0.105 mmol) is added followed bycatalytic NaCN (˜1 mg). After 2 hours, 2 mL THF is added to assist withsolubility. After stirring for 16 hours at room temperature, a secondequivalent of tosylmethyl isocyanide (0.020 g, 0.105 mmol) is added.After 8 hours, the reaction mixture is concentrated under reducedpressure and used as is in the next reaction: LC/MS ESI (+) m/z 671, 669(M+Br pattern) detected.

Step B:(4-Bromo-2-chloro-phenyl)-[4-fluoro-6-(3H-imidazol-4-yl)-1H-benzoimidazol-5-yl]-amine10aa:(4-Bromo-2-chloro-phenyl)-{4-fluoro-1-(2-methanesulfonyl-ethyl)-6-[4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-1H-benzoimidazol-5-yl}-amine10bb (0.072 g, 0.107 mmol) is treated with 2.4 mL of a 2.0 M NH₃ in MeOHsolution in a sealed pressure tube. The reaction mixture is then heatedto 90° C. with stirring for 20 hours and furthered stirred at roomtemperature for 3 days. The reaction mixture is transferred to a roundbottom flask and concentrated under reduced pressure. Purification byflash column chromatography, twice, eluted with 10:1 methylenechloride:MeOH, followed by successive triturations with methylenechloride and then diethyl ether provides 3 mg (7%) desired product:LC/MS ESI (+) m/z 408, 406 (M+Br pattern) detected; ¹H NMR (400 MHz,MeOH-d₄)

8.23 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.46 (m, 1H), 7.32 (d, 1H),7.05 (m, 1H), 6.20 (dd, 1H).

Example 52

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide (10cc)

Step A: 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a:3-Chloro-2,4-difluoro-benzoic acid 1a (3.00 g, 15.6 mmol) is added to astirred solution of concentrated H₂SO₄ (16 mL) and fuming nitric acid(0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellowslurry is poured onto ice water (100 mL). The aqueous mixture isextracted with diethyl ether (3×). The organic extracts are dried(Na₂SO₄) and concentrated under reduced pressure to give 3.50 g (95%) ofclean desired product as a pale yellow solid.

Step B. 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a: Ammoniumhydroxide solution (6.88 g, ˜30% in water, 58.9 mmol) is added to asolution of 3-chloro-2,4-difluoro-5-nitro-benzoic acid 2a (3.5 g, 14.7mmol) in water (16 mL) at 0° C. with stirring. Upon completion of theammonium hydroxide addition the reaction mixture is warmed to roomtemperature. After 5 hours the reaction mixture is cooled to 0° C. andconcentrated HCl is carefully added until the pH of the reaction mixtureis near zero. The solid is collected by filtration and washed with waterand diethyl ether. The solids are transferred to a round bottom flask asa solution in MeOH and EtOAc and concentrated under reduced pressure togive 2.96 g of a yellow solid. The filtrate is partitioned betweendiethyl ether and water and the organic layer is washed with brine. Thecombined organic extracts are dried (Na₂SO₄) and concentrated underreduced pressure to give 0.65 g of product. Recovered a total of 3.61 g(104%) of pure desired product that is carried forward without furtherpurification.

Step C: 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a:To a stirred solution of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid3a (3.61 g, 15.4 mmol) in THF (30 mL) and MeOH (10 mL), TMS diazomethane(9.23 mL, 2.0 M solution in hexanes, 18.5 mmol) is added. Aftercompletion of reaction, the reaction mixture is concentrated via rotaryevaporation with acetic acid in the trap. The recovered oily solid istriturated with diethyl ether to provide 1.51 g of a yellow solid. Thefiltrate is concentrated and triturated with diethyl ether to give anadditional 0.69 g of yellow solid. A total of 2.20 g (57%) of puredesired product is recovered.

Step D: 4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester5c: 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a (2.20g, 8.84 mmol) is suspended in MeOH (9.4 mL) and aniline (3.22 mL, 35.4mmol) is added. The reaction mixture is heated to reflux with stirringunder a nitrogen atmosphere. After 19 hours, the reaction is complete.Distilled water (3.22 mL) is added to the reaction mixture and refluxingis continued for one hour. The reaction mixture is cooled to 0° C. in anice bath for 20 minutes. The reaction mixture is filtered and washedwith 3:10 distilled water/MeOH (65 mL total) and then with MeOH. Thesolid is dissolved with CH₂Cl₂ and concentrated under reduced pressureto give 2.40 g (84%) of pure desired product. MS APCI (−) m/z 320.3(M−1) detected.

Step E: 4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b:4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c(0.50 g, 1.55 mmol) is dissolved into 2:1 EtOH/MeOH (15.5 mL). Saturatedaqueous NH₄Cl (15 mL), Zn powder (1.02 g, 15.6 mmol), and THF (10 mL)are added. After stirring for 20 hours, the reaction mixture is dilutedwith CH₂Cl₂/THF and water. The organic layer is washed with water (3×).The combined organic extracts are dried (Na₂SO₄) and concentrated underreduced pressure. The solids are triturated with ether to give 0.32 g(70%) clean desired product.

Step F: 7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acidmethyl ester 7c: 4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methylester 6b (0.32 g, 1.09 mmol) and formamidine acetate (72 mg, 1.64 mmol)in EtOH (36 mL) are heated, with stirring, to 80° C. After 44 hours, thereaction mixture is cooled to room temperature and diluted with EtOAcand washed with water (3×), saturated NaHCO₃, and brine. The combinedorganic extracts are dried (Na₂SO₄) and concentrated under reducedpressure to give 0.33 g (99%) clean desired product as a solid. MS APCI(+) m/z 302.3 (M+1) detected.

Step G: 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylicacid methyl ester 8g:7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester7c (0.327 g, 1.08 mmol) is dissolved into DMF (16 mL) and NBS (0.193 g,1.08 mmol) is added. After one hour, the reaction mixture is quenched bythe addition of saturated aqueous NaHSO₃. The reaction mixture is thenpartitioned between EtOAc/THF and water. The organic layer is washedwith water and brine. The combined organic extracts are dried (Na₂SO₄)and concentrated under reduced pressure. The recovered solid istriturated with ether to give 0.225 g (54%) pure desired product. MS ESI(+) m/z 382, 384 (M+, Br pattern) detected.

Step H:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylicacid methyl ester 10dd:6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acidmethyl ester 8g (0.225 g, 0.591 mmol) is dissolved in DMF (2 mL) and NCS(79 mg, 0.591 mmol) is added. After the NCS is in solution concentratedHCl (0.005 mL, 0.059 mmol) is added. After 2 hours, sodium bicarbonate,water and NaHSO₃ are added to the reaction mixture. Solids are filteredand washed with water and ether to give 0.141 g (57%) of clean desiredproduct as a tan solid. MS APCI (−) m/z 414, 416 (M−, Br pattern)detected.

Step I:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid methyl ester 10ee:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylicacid methyl ester 10dd (0.141 g, 0.34 mmol), potassium carbonate (0.141g, 1.02 mmol), and iodomethane (0.063 mL, 1.02 mmol) are dissolved indimethylformamide (3 mL). After 20 hours, the reaction mixture isdiluted with EtOAc and washed with water (3×), potassium carbonate, andbrine. The organic layer is dried (Na₂SO₄) and concentrated to a brownoil. The N3 and N1 alkylated regioisomers are separated by flashchromatography (EtOAc). The recovery of the N3 alkylated regioisomer is20.4 mg (28%). MS ESI (+) m/z 428, 430 (M+, Br pattern) detected.

Step J:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid 10ff:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid methyl ester 10ee (21 mg, 0.048 mmol) is dissolved into 2:1THF/water (1.2 mL) and NaOH (0.190 mL, 1.0 M aqueous solution, 0.190mmol) is added. After stirring for 4 hours the reaction is diluted withwater and acidified to pH 2 by addition of 1.0 M HCl. The mixture isthen extracted with 3:1 EtOAc/THF (3×), dried (Na₂SO₄) and concentratedto give quantitative yield of desired product as a white solid. MS APCI(+) m/z 414, 416 (M+, Br pattern) detected.

Step K:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-vinyloxy-ethoxy)-amide 10gg:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid 10ff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.010mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL,0.077 mmol), and EDCI (19 mg, 0.10 mmol) are dissolved intodimethylformamide (1.0 mL) and allowed to stir under a nitrogenatmosphere at room temperature for 24 hours. The reaction mixture isdiluted with EtOAc, washed with water (3×), 10% potassium carbonate(2×), saturated ammonium chloride, brine, dried (Na₂SO₄), andconcentrated under reduced pressure to give 39 mg of 85% pure material.MS APCI (−) m/z 497, 501 (M−, Br pattern) detected.

Step L:6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide 10 cc: Hydrochloric acid (0.78 mL, 1.0 Maqueous solution, 0.78 mmol) is added to a suspension of6-(4-bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylicacid 10gg (2-vinyloxy-ethoxy)-amide (39 mg, 0.078 mmol) in MeOH (1 mL).After one hour, the reaction mixture is neutralized to pH 7 andconcentrated under reduced pressure. The solids are dissolved in EtOAc,washed with brine, dried (Na₂SO₄), and concentrated under reducedpressure. Flash chromatography (20:1 CH₂Cl₂/MeOH) provided 9 mg (23%) ofpure product: MS APCI (+) m/z 473, 475 (M+, Br pattern) detected; ¹H NMR(400 MHz, CDCl₃) δ 8.30 (s, 1H), 8.08 (s, 1H), 7.57 (d, 1H), 7.15 (dd,1H), 6.21 (d, 1H), 3.97 (s, 3H) 3.86 (m, 2H), 3.57 (m, 2H).

Example 53

6-(4-Bromo-2-chloro-phenylamino)-3H-benzoimidazole-5-carboxylic acid(2-hydroxy-ethoxy)-amide (10hh)

The above compound is prepared in an analogous fashion to Example 52except that Step I is eliminated. MS APCI (−) m/z 457, 461 (M-, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.85 (s, 1H),7.50 (d, 1H), 7.14 (dd, 1H), 6.21 (d, 1H), 3.84 (m, 2H), 3.61 (m, 2H).

Example 54

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-2-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide (10ii)

Step A: 4,5-Diamino-3-fluoro-2-phenylamino-benzoic acid methyl ester 6c:4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 26a(11.44 g, 37.48 mmol) is suspended in ethanol (400 mL) and ammoniumformate (11.80 g, 187.0 mmol) and 20% Pd(OH)₂/C (10.00 g, 18.79 mmol)are added. The reaction mixture is stirred at 95° C. under N₂ for 30minutes. The reaction mixture is cooled to room temperature and thenfiltered through celite, rinsing with ethanol. The filtrate isconcentrated under reduced pressure to give 9.63 g (93%) of the puredesired product as a purple/red solid. MS ESI (+) m/z 276 (M+1)detected.

Step B: 7-Fluoro-2-methyl-6-phenylamino-3H-benzoimidazole-5-carboxylicacid methyl ester 31a: 4,5-Diamino-3-fluoro-2-phenylamino-benzoic acidmethyl ester 6c (0.20 g, 0.73 mmol) is suspended in ethanol (3 mL) and 5M aqueous HCl (1 mL., 5.00 mmol) is added. The reaction mixture isbrought to reflux under N₂ and then 2,4-pentanedione (0.150 mL, 1.45mmol) is added. The reaction mixture is stirred at reflux for 60minutes. The reaction mixture is cooled to room temperature and treatedwith saturated aqueous NaHCO₃ until the pH of the reaction mixture is pH7 and is then concentrated under reduced pressure to dryness. Theresidue is diluted with ethyl acetate and water, poured into aseparatory funnel and the layers separated. The ethyl acetate layer iswashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure. The red solid residue is triturated with diethyl ether toyield a light brown solid and a red filtrate. The solid is collected andwashed with diethyl ether to yield 0.20 g (91%) of the pure desiredproduct as a light brown solid. MS ESI (+) m/z 300 (M+1) detected.

Step C:6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-2-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide 10ii:7-Fluoro-2-methyl-6-phenylamino-3H-benzoimidazole-5-carboxylic acidmethyl ester 31a is converted by the bromination, chlorination,hydrolysis, coupling, and hydrolysis procedures already described toyield the pure desired product as an off-white solid. MS ESI (+) m/z457, 459 (M+, Br pattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.58 (s,1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.41 (m, 1H), 3.91 (t, 2H), 3.65 (t,2H), 2.61 (s, 3H); ¹⁹F NMR (376 MHz, CD₃OD) −135.84 (s).

Example 55

6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethyoxy-amide (11yy)

Step A:7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester 10jj:7-Fluoro-6-o-tolylamino-1H-benzoimidazole-5-carboxylic acid methyl ester7a (1.47 g, 4.92 mmol) is suspended in 1:1 THF:MeOH mixture (44 mL) andcooled to −78° C. under a nitrogen atmosphere. A solution of NIS (1.66g, 7.39 mmol) in THF (2 mL) is added followed by a MeOH (2 mL) solutionof TsOH—H₂O (1.87 g, 9.84 mmol). After 30 minutes, the reaction mixtureis warmed to 0° C. and 1 mL methylene chloride is added. The reaction isslowly allowed to warm to room temperature with stirring over 16 hours.The reaction mixture is quenched by the addition of 10% Na₂S₂O₄solution. The reaction mixture is then diluted with water and ethylacetate and the layers separated. The aqueous layer is extracted withethyl acetate. The combined organic extracts are dried (Na₂SO₄) andconcentrated under reduced pressure. The recovered solid is trituratedwith MeOH to give 1.45 g (69%) pure desired product: MS ESI (+) m/z 426(M+1) detected; MS ESI (−) m/z 424 (M−1) detected.

Step B:7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid methyl ester 10kk:7-Fluoro-6-(4-iodo-2methyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester 10jj (0.200 g, 0.470 mmol) is suspended in DMF (2 mL)under N₂ and cooled to 0° C. in an ice-water bath. NaH (60% dispersionin oil, 0.018 g, 0.470 mmol) is added. After 10 minutes, the reactionmixture is warmed to room temperature and stirred for 30 minutes. Aftercooling to 0° C., SEMCl (0.087 mL, 0.494 mmol) is added and the reactionis allowed to warm to room temperature with stirring overnight. Thereaction mixture is quenched by the addition of water and brine. Thereaction mixture is extracted with ethyl acetate. The combined organicextracts are washed with water and brine, and dried (MgSO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography eluted with 1:1 hexanes:ethyl acetate provides 0.182 g(70%) of desired product as a 1:1 mixture of N1 and N3 isomers as awhite foam.

Step C:6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid methyl ester 10ll: To a stirred solution of a 1:1 mixture of N1:N3isomers of7-fluoro-6-(4-iodo-2-methyl-phenylamino)-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid methyl ester 10jj (0.060 g, 0.108 mmol) in 1 mL DMF at roomtemperature under N₂ is added dppf (2 mg, 0.004 mmol) followed by Pd₂dba₃ (2 mg, 0.002 mmol) and Zn(CN)₂ (8 mg, 0.065 mmol) (TetrahedronLett. 1999, 40, 8193-8195). The reaction mixture is heated to 120° C.for 45 minutes. The reaction mixture is cooled to room temperature andquenched by the addition of 5 mL of a 4:1:5 mixture of sat NH₄Cl:concNH₄OH:water. The aqueous layer is extracted with ethyl acetate. Thecombined organic extracts are washed with water (3×), brine, and dried(MgSO₄) and concentrated under reduced pressure. Purification by flashcolumn chromatography eluted with 1:1 hexanes:ethyl acetate provides 38mg (77%) of desired product as a 1:1 mixture of N1 and N3 isomers: APCIMS (+) m/z 455 (M+1) detected.

Step D:6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid 10 mm: A 1:1 mixture of N1:N3 isomers of6-(4-cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid methyl ester 10ll (31 mg, 0.068 mmol) is hydrolyzed with aqueoussodium hydroxide as described previously to give 26 mg (87%) of desiredproduct.

Step E:6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid cyclopropylmethyoxy-amide 11zz: A 1:1 mixture of N1:N3 isomers of6-(4-cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid 10 mm (26 mg, 0.059 mmol) is coupled with EDCI and cyclopropylmethyl hydroxylamine hydrochloride as described previously to give 28 mg(93%) of desired product: APCI MS (+) m/z 510 (M+1) detected.

Step F.:6-(4-Cyano-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethyoxy-amide 11yy: To a slurry of a 1:1 mixture ofN1:N3 isomers6-(4-cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylicacid cyclopropylmethyoxy-amide 11zz (28 mg, 0.055 mmol) in 0.5 mL EtOHis added 0.5 mL 10% HCl. The reaction mixture is heated to 50° C. withstirring overnight (Whitten et al., J. Org. Chem., 1986, 51, 1891-1894).An additional 0.5 mL 10% HCl is added and the reaction mixture stirredat 700C overnight. The reaction mixture is cooled to room temperatureand neutralized to pH ˜8 with 1.5 mL 1N NaOH. The reaction mixture isextracted with ethyl acetate, dried (MgSO₄) and concentrated underreduced pressure to give 14 mg (60%) of 90% pure product as a mixture ofrotatomers: MS APCI (+) m/z 380 (M+1) detected; MS APCI (−) m/z 378(M−1) detected; ¹H NMR (400 MHz, MeOH-d₄) δ 8.41 (bs, 1H), 7.75 (m, 1H),7.50 (s, 1H), 7.38 (d, 1H), 6.51 (m, 1H), 3.72 (d, 0.5H), 3.65 (d,1.5H), 2.41 (s, 3H), 0.98 (1H, m), 0.58 (d, 1.5H), 0.40 (d, 0.5H), 0.25(d, 1.5H), 0.19 (d, 0.5H).

Example 56

6-(4-Ethynyl-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11aaa

Step A:7-Fluoro-6-(2-methyl-4-trimethylsilanylethynyl-phenylamino)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11bbb:7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11ccc (0.025 g, 0.052 mmol) is dissolvedin 1:1 acetonitrile/triethylamine (0.50 mL). Ethynyl-trimethylsilane(0.013 mL, 0.092 mmol), Pd(PPh₃)₂Cl₂ (0.004 g, 0.006 mmol), and CuI(0.002 g, 0.011 mmol) are added consecutively and the reaction mixtureis stirred at 60° C. for 1 hour under N₂. The reaction mixture is cooledto room temperature and concentrated under reduced pressure. The residueis purified by FCC (eluting with 20:1 methylene chloride:methanol) toyield 0.020 g (87%) of the desired product.

Step B:6-(4-Ethynyl-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11 aaa:7-Fluoro-6-(2-methyl-4-trimethylsilanylethynyl-phenylamino)-3H-benzoimidazole-5-carboxylicacid cyclopropylmethoxy-amide 11bbb (0.020 g, 0.044 mmol) is dissolvedin tetrahydrofuran (0.50 mL) and the reaction solution is cooled to 0°C. TBAF (50 uL, 0.050 mmol, 1 M solution in tetrahydrofuran) is added.The reaction mixture is warmed to room temperature and additional TBAF(25 uL, 0.025 mmol, 1 M solution in tetrahydrofuran) is added. Thereaction mixture is stirred at 50° C. for 2 hours under N₂. The reactionmixture is cooled to room temperature, a few drops of H₂O are added andthen it is concentrated under reduced pressure. The residue is purifiedby FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.011 g(65%) of the pure desired product. MS APCI (−) m/z 377 (M−1) detected;¹H NMR (400 MHz, CDCl₃) δ 10.56 (broad s, 1H), 8.12 (s, 1H), 7.99 (s,1H), 7.28 (s, 1H), 7.11 (d, 1H), 6.42 (broad, 1H), 3.70 (br s, 2H), 2.96(d, 1H), 2.37 (s, 3H), 0.85 (m, 1H), 0.50 (m, 2H), 0.22 (m, 2H).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

1. A compound which is6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxyethoxy)-amide or a pharmaceutically acceptable saltthereof.